Introduction to HIV
Contents Introduction The origin of Aids Terminology Classification Disease progression Transmission Sexual transmission Injection drug use related HIV infection Transmission of HIV by blood, blood products, tissue transplantation and artificial insemination Vertical transmission HIV testing The replication cycle of HIV-1 Virus entry Reverse transcription Integration of the viral DNA into cellular genomic DNA Viral protein expression Virus assembly Expression of viral envelope proteins Structure of the HIV virus Structural proteins Gag proteins Gag-Pol precursor HIV-1 protease Reverse transcriptase Integrase Envelope proteins Regulator proteins Tat Rev Accessory proteins Nef Vpr Vpu Vif The regulation of HIV gen expression Clinical course of untreated HIV disease Primary infection Transmission Aborted HIV infection Establishing infection Early Impact on T Cell Clones, T Cell Diversity, and Loss of Members of the T Cell Repertoire The syndrome of Primary HIV infection Early and middle stages of HIV disease Advanced HIV disease Late stage HIV disease Clinical manifestations of HIV disease Fever Wasting Oral manifestations of HIV disease Dermatologic manifestations of HIV infection Neurological dysfunction's Entry into the central nervous system Pathogenesis of Aids Dementia Complex (ADC) Cerebral symptoms and signs Symptoms affecting cord nerve roots and muscle Pain in Aids Respiratory syndromes in HIV disease Cardiac involvement in HIV disease Endocrine abnormalities Hepatologic abnormalities Renal manifestations in HIV infection Gastrointestinal manifestation in HIV infection Ophthalmic manifestations in HIV infection Otolaryngologic manifestations in HIV infection Infections and malignancies associated with HIV disease Infections Malignancies

Introduction

HIV is the abreviation used for the Human Immunodeficiency Virus. HIV attacks the body's immune system. Normally, the immune system produces white blood cells and antibodies that attack viruses and bacteria. The infection fighting cells are called T-cell lymphocytes. Months to years after a person is infected with HIV, the virus destroys all the T-cell lymphocytes. This disables the immune system to defend the body against diseases and tumors. Various infections will be able to develop, these opportunistic infections take advantage of the body's weakened immune system. These infection which normally won't cause severe or fatal health problems will eventually cause the death of the HIV patient. (1)

The origin of aids

At this time, most evidence suggest that AIDS has it roots in Africa. This is believed because certain Simian Immunodeficiency Viruses (SIVs) are closely related to HIV and HIV-2, for instance, has an almost exact counterpart in a virus of the sooty-mangabey, a type of African monkey. (2) The HIV-2's connection to the sooty mangabey is probably the most compelling evidence for animal to man transfer of HIV. A likely source of HIV-1 has been more difficult to pin down. The closest simian virus to HIV-1 discovered to date exists in certain chimpanzees. (3). Scientists have long recognized the ability of certain viruses and other diseases to pass from animals to humans. This process is referred to as zoonosis. Once an animal disease has infected people, it may then be passed from human to human. Although it has not been proven that HIV came from primates, an SIV has been known to infect humans. (4)
The earliest and most compelling evidence of HIV infection is that of an adult male who lived in what is now the Democratic Republic of Congo. Scientists recently succeeded in isolating the virus from a plasma sample taken from the man in 1959. Researchers believe that the ancestor of this strain may date to the 1940s or 50s and was introduced into humans a decade or more earlier. (5)
In June and July of 1981, cases of an extremely uncommon opportunistic infection, Pneumocystis carinii pneumonia, and a very rare skin tumor of endothelial cell origin, Kaposi's sarcoma, were first reported in New York and California in epidemic proportions among previously healthy young homosexual and bisexual men who were not previously known to be predisposed to these diseases. (6) With the rapidly increasing number of cases, it was soon recognized that other life threatening infections and neoplastic diseases were also observed and found to be associated with an unexplained defect in cell mediated immunity, common to each of these patients. (6)
By early 1982 the group of disease entities was named the acquired immune deficiency syndrome (AIDS) by the Center for Disease Control (CDC). (6) The term "syndrome" has been used because AIDS does not constitute a single illness, but rather encompasses a wide range of clinical diseases including specific life threatening infections and neoplasm's associated with a profound and irreversible unexplained acquired disorder of cell mediated immunity. Since  the appearance of the original definition in September of 1982, the CDC has subsequently revised this definition to accommodate additional syndromes recognized as manifestations of advanced HIV disease. (7)
When the first cases of AIDS were reported, many hypotheses were proposed to explain the possible cause(s) of the newly recognized syndrome, but it is now widely accepted that AIDS is caused by a previously unknown human retrovirus, which was initially discovered and isolated in 1983 from patients with persistent generalized lymphadenopathy at the "Institut Pasteur" in Paris. (6)
All the related viruses which were discovered were named the human immunodeficiency virus (HIV) by the International Committee on the Taxonomy of Viruses in 1986. (6)

Terminology (8)

Untreated HIV disease is a chronic progressive process that begins with infection, is often followed by a "primary HIV syndrome," and progresses in adults over a median period of more than 10 years to the late stage: AIDS. From the time of infection, the virus continuously and rapidly replicates, mutates, and as a result diversifies and evolves in response to selective pressure. Immune system damage also begins upon infection. The burden of virus and the bulk of this process occurs in lymphoid tissue, and the immune system struggles to hold the process in check. Slowly, but relentlessly, the process destroys essential components of the host immune system. Progression is often accelerated in infants with prenatal HIV infection. Eventually the host becomes increasingly susceptible to and eventually dies as a result of complications of opportunistic infections and malignancies resulting from immune system dysfunction.

AIDS: The syndrome called AIDS (Acquired Immuno Deficiency Syndrome) is the late stage of HIV disease. (see classification)

ARC: The term AIDS Related Complex has been abandoned, because the signs labeled with this term are manifestations of the middle stage of HIV disease.

PGL: The Progressive Generalized Lymphadenopathy syndrome is a common manifestation of early and middle stage HIV disease but it has no prognostic significance.

The CDC classification of HIV disease was first put forth as a categorization of HIV related symptoms into four groups and was explicitly for "public health purposes" and not "intended as a staging system," (9) although it was frequently treated as if it were a staging system in the AIDS literature. Staging is disease classification that aims primarily to make groupings that have different prognosis and can be used in guiding treatment decisions. Stages attempt to classify disease in a progressive sequence from least to most severe, each higher stage having a poorer prognosis or different medical management than the preceding stage. The current CDC classification system (see annex 1), from the revision in 1993, combines three categories of the CD4 count with three symptom categories and is closer to a staging system but is still not described as such. (7) The CDC, however, proposed that it be used to "guide clinical and therapeutic actions in the management of HIV infected adolescents and adults." (7) This description of its intended use is close to the use of a staging system. (10)
 

Disease progression (11)

HIV disease is a continuum of progressive damage to the immune system from the time of infection to the manifestation of severe immunologic damage by opportunistic infections, neoplasm's, wasting, or low CD4 lymphocyte count that define AIDS. Nearly all infected persons have a CD4 lymphocyte count below the mean for seronegative persons and show a a progressive loss of these cells over time. (12) Most HIV positive persons, even with near normal CD4 lymphocyte counts, show functional lymphocyte abnormalities that suggest their long term immune functioning will be impaired. (13) Rates of progression to AIDS are very low in the first 2 years after infection and increase thereafter. The median incubation period from HIV infection until development of AIDS is estimated at approximately 10 years for young adults. (14) The incubation period  is known as the period from infection to development of AIDS. The estimate varies with the age at which infection occurs and is significantly shorter in infants and in older adults and varies even between infection at age 20 and infection at age 40. (15) The time from first diagnosis of AIDS to death has been characterized separately from the incubation time from infection to AIDS as AIDS survival time. In the Multicenter Hemophilia Cohort Study median survival after a single AIDS defining condition ranged from 3 to 51 months for the 10 most common conditions. (16) The addition of a CD4 lymphocyte count less than 200/µl as an AIDS defining condition in 1993 further broadened the range of AIDS survival times because most of the AIDS defining disease diagnoses occur at lower CD4 lymphocyte counts. The time from HIV infection to a CD4 lymphocyte  count less than 200/µl is on average nearly 2 years less than to manifestation of an AIDS defining opportunistic infections. (17)

Transmission

Sexual transmission (18)
The current worldwide expansion of the AIDS epidemic is primarily driven by the sexual transmission of human immunodeficiency virus type 1 (HIV-1), and its future will be determined largely by the degree to which sexual transmission can be reduced. Although sexual transmission among homosexual males is still a significant part of epidemic spread, in the most populous regions of the world, sexual transmission among heterosexuals is the dominant mode of spread. (19) HIV-2 is thought to be less infectious than HIV-1, although few data are available. HIV-2 infected individuals generally have a lower viral titer in peripheral blood samples than those infected with HIV-1, and incidence rates of infection appear lower in cohorts at risk for HIV-2 than among comparable populations at risk for HIV-1. (20) HIV is commonly transmitted sexually by penile anal intercourse and penile vaginal intercourse and infrequently by fellatio. Vaginal intercourse can transmit HIV to either the male or the female partner, but a number of studies have shown that the risk is higher to the female partner. (21) Studies of homosexual men have shown consistently that the receptive partner in anal intercourse is at the highest risk of HIV infection and that risk is strongly related to the number of male sexual partners. (22) Anal intercourse has also been shown to be a risk factor for the female partner in heterosexual studies. (23) Presumably, fellatio would pose the same risk to the female partner as to the receptive oral partner in male homosexual couples, but data are lacking on the risk in heterosexuals. There is a theoretic potential of transmission from cunnilingus, but no well documented cases have been reported. Condom use has been shown to reduce sexual transmission of HIV. A meta-analysis of several studies of HIV transmission found that condom efficacy was 69% overall. (24) Condom efficacy is greatly increased by proper use. The female condom has been approved by the Food and Drug Administration to provide a method of contraception that is more under the woman's control that should also protect against HIV. In a laboratory study, use of zidovudine was associated with decreased detection of HIV-1 in semen, (25) and in a prospective study of male-to-female transmission, controlling for disease stage, men taking zidovudine were less likely to transmit HIV to their female partner than were men not receiving antiretroviral therapy. (26) Antiretroviral therapy thus may reduce infectiousness.

Injection drug use related HIV infection
Transmission of HIV among injection drug users occurs primarily through HIV infected blood contamination of injection paraphernalia, which is re-used by an uninfected injection drug users. Behaviors that increase the likelihood, frequency, and magnitude of exposure to infected blood increase the risk of infection. Among injection drug users, several demographic and behavioral characteristics are associated with greater risk of acquiring HIV. Foremost among risk factors is the sharing of needles, syringes, and other injection equipment. Sharing is a common practice among injection drug users worldwide. (27)

Transmission of HIV by blood, blood products, tissue transplantation and artificial insemination (#28)
Transmission of HIV-1 and some other viruses can occur following transfusion of a blood product derived from an infected person's blood and processed into a blood component (i.e., whole blood, packed red cells, fresh frozen plasma, cryoprecipitate, and platelets). (29) Plasma derived blood products, which are manufactured from pooled plasma can transmit HIV-1 and other viruses depending on the production process. (30) HIV has been transmitted through transplantation of kidney, liver, heart, pancreas, bone, and skin: all blood containing organs or highly vascular tissues. There are no reports of HIV tissue transmission from HIV-seropositive donors of cornea, ethanol treated and lyophilized bone, fresh frozen bone without marrow, lyophilized tendon or fascia, or lyophilized and irradiated dura mater. (31) Both intrauterine insemination and cervical insemination result in HIV transmission.

Vertical Transmission
Perinatal transmission of human immunodeficiency virus accounts for virtually all new HIV infections in children. (32) The relative contributions of in utero and intrapartum HIV transmission are unknown. One proposed scheme for differentiating these 2 modes of transmission suggest that the virus was transmitted early or in utero if HIV is detected in the infant within the first 48 hours of live. (33) Late or intrapartum transmission is said to have occurred if virologic evaluations are negative during the first week of life but there is subsequent HIV detection between 7 and 90 days of age. Applying these admittedly speculative definitions to published studies suggest that 50% to 70% of HIV vertical transmission occurs intrapartum. If true, this finding has important implications for designing strategies to interrupt transmission. Breast feeding substantially increases the risk of HIV vertical transmission, (33) therefore bottle feeding is currently recommended for all infants born to HIV infected mothers. (33)

HIV testing

Testing serum for antibodies to HIV with a standard ELISA (followed by a confirmatory Western Blot) is currently the most common, cost effective, and accurate method of screening for infection. (34) Rapid serum HIV antibody tests, saliva- and urine- based antibody tests, and home HIV antibody testing kits have been approved by the Food and Drug Administration (FDA) and are being marketed. (35) HIV RNA tests are being used in research and clinical settings to diagnose primary HIV infection before the formation of detectable antibodies. (36)
Although HIV antibody tests are the most appropriate for identifying infection, alternate technologies can contribute to an accurate diagnosis, assist in monitoring the response to therapy, and can be used to effectively predict disease outcome. The p24 antigen assay measures the viral capsid (core) p24 protein in blood that is detectable earlier than HIV antibody during acute infection. It occurs early after infection due to the initial burst of virus replication and is associated with high levels of viremia during which the individual is highly infectious. (37)
The last 5 years has seen an enormous revolution in the clinical virology laboratory: the development and rapid application of widely available, sensitive, and precise nucleic acid amplification assays for the measurement of "viral load" (i.e., plasma HIV-1 RNA) in HIV1 infected patients. Quantitative laboratory methods that measure HIV-1 "viral load" or "viral burden" can best be described as assays that assess the level of overall virus replication activity that is reflective of the underlying disease process in the infected patient, usually by quantification of plasma HIV-1 RNA. (38)

The replication Cycle of HIV-1 (39)
 

This picture is clickable, if there is information needed about one of the sections click on it.

This picture was found at http://www.courses.ahc.umn.edu/medical-school/IDis/Images/lentivirus_drawing.jpg

Virus entry
Several independent lines of evidence demonstrated that CD4 serves as a binding receptor for HIV-1, which bind with high affinity to gp120. (40) Gp120 is a viral surface envelope protein. The post binding events required for HIV-1 and cell membrane fusion are not well understood. HIV-1, like most other retroviruses, infects cells in a pH-independent manner that is consistent with direct fusion between viral and cell surface membranes. (41)

Reverse transcription
The reverse transcription pathway generates a linear DNA copy of the viral RNA genome. (42) This step takes place within a viral nucleoprotein complex and requires the coordinated activities of reverse transcriptase, an RNA- and DNA dependent DNA polymerase, and RNaseH, which degrades the RNA component of RNA-DNA hybrid molecules. Because the viral nucleoprotein complexes are rapidly transported to the host cell nucleus, the majority of viral DNA synthesis occurs within the nuclear compartment.

Integration of the viral DNA into cellular genomic DNA
The nuclear viral complexes serve as the machines that integrate viral DNA into host cell chromosomal DNA to form a provirus. This step is critically dependent on the activity of the viral integrase protein and is essential for viral gene expression. (43)

Viral  protein expression
The expression of viral genes requires the collaborative activities of the host cell transcription machinery (RNA polymerase and transcription factors Sp1 and NFkB) and viral regulatory proteins (tat and rev).

Virus assembly
The MA gag protein seems to specify the site of viral assembly. Membrane attachment of viral gag and gag-pol precursor proteins requires N-terminal cotranslational addition of myristic acid to viral MA proteins. (44) Although MA contains the membrane binding domain and can induce membrane budding, the incorporation of gag and gag-pol precursor proteins into functional viral particles requires the presence of interaction domains of gag and a late acting L-domain of the p6 gag protein. (45) In retroviruses, viral genomic RNA is selectively taken up from the pool of cytoplasmic RNAs because the NC gag protein recognizes specific cis-acting RNA packaging signals.

Expression of viral envelope proteins
Retroviral envelope proteins are synthesized in the endoplasmic reticulum (ER) of infected cells and are transported to the cell surface by the host cell secretory pathway. Within the endoplasmatic reticulum, monomers of gp160, the precursor HIV envelope protein, associate with BiP, a molecular chaperone, before folding and oligomerization. Oligomeric gp160 complexes are transported from the endoplasmatic reticulum to the Golgi apparatus, where gp160 is cleaved by a cellular proteinase to produce the surface gp120 and transmembrane gp41 sub units before transport to the cell surface. (46) During or shortly after budding, retroviral particles mature when the gag and gag-pol poly proteins are cleaved to mature protein products by the viral PR. The mature virions that are released from the virus producer cells are then competent to begin the replication cycle again in other target cells.

Structure of the HIV virus (47)
 

The integrated form of HIV-1, also known as the provirus, is approximately 9.8 kilobases in length. The genes of HIV are located in the central region of the proviral DNA and encode at least nine proteins.

Structural proteins

Gag proteins:
The gag gene gives rise to the 55 kilodalton Gag precursor protein, also called p55, which is expressed from the unspliced viral mRNA. After budding, p55 is cleaved by the virally encoded protease during the process of viral maturation into four smaller proteins designated MA (matrix [p17]), CA (capsid [p24]), NC (nucleocapsid [p9]), and p6.
Most MA molecules remain attached to the inner surface of the virion lipid bilayer, stabilizing the particle. A small percentage of MA, however, binds integrase, and is thereby recruited inside the deeper layers of the virion. (48) These MA molecules subsequently facilitate the nuclear transport of the viral genome because a karyophillic signal on MA is recognized by the cellular nuclear import machinery. This phenomenon allows HIV to infect non dividing cells, an unusual property for a retrovirus. (49)
The p24 (CA) protein forms the conical core of viral particles. Cyclophilin A has been demonstrated to interact with the p24 region of p55 leading to its incorporation into HIV particles. (50)
The NC region of Gag is responsible for specifically recognizing the so-called packaging signal of HIV. (51) The packaging signal consists of four stem loop structures located near the 5' end of the viral RNA, and is sufficient to mediate the incorporation of a heterologous RNA into HIV-1 virions. (52) NC also facilitates reverse transcription. (53)

Gag-Pol precursor:
The viral protease, integrase, RNAse H, and reverse transcriptase are always expressed within the context of a Gag-Pol fusion protein. During viral maturation, the virally encoded protease cleaves the Pol polypeptide away from Gag and further digests it to separate the protease (p10), RT (p50), RNAse H (p15), and integrase (p31) activities.

HIV-1 protease:
The HIV-1 protease is an aspartyl protease (54) that acts as a dimer. Protease activity is required for cleavage of the Gag and Gag-Pol polyprotein precursors during virion maturation.

Reverse transcriptase:
The pol gene encodes reverse transcriptase. During the process of reverse transcription, the polymerase makes a double stranded DNA copy of the dimer of single stranded genomic RNA present in the virion.

Integrase:
The integrase protein mediates the insertion of the HIV proviral DNA into the genomic DNA of an infected cell.

Envelope proteins:
The 160 kD Env (gp160) is expressed from singly spliced mRNA. A cellular protease cleaves gp160 to generate gp41 and gp120. Gp41 contains the transmembrane domain of Env, while gp120 is located on the surface of the infected cell and of the virion through non covalent interactions with gp41. Env exists as a multimer, most likely a trimer, on the surface of the cell of the virion. (55) Interactions between HIV and the virion receptor, CD4, are mediated through specific domains of gp120.

Regulator proteins

Tat:
Tat is a transcriptional transactivator that is essential for HIV-1 replication.Tat is an RNA binding protein, unlike conventional transcription factors that interact with DNA. (56) The mechanism of Tat function remains controversial. From some studies, it appears that Tat acts principally to promote the elongation phase of HIV-1 transcription, (57) other studies indicate that Tat may be involved in the phosphorylation of the carboxyl terminal domain (CTD) of RNA polymerase II. (58)

Rev:
Rev is a 13-kD sequence-specific RNA binding protein. Rev acts to induce the transition from the early to the late phase of HIV gene expression.

Accessory proteins

Nef:
Nef has been shown to have multiple activities, including the down regulation of the cell surface expression of CD4, (59) the perturbation of T-cell activation, (60) and the stimulation of HIV infectivity. (61)

Vpr:
The Vpr protein is incorporated into viral particles. Vpr plays a role in the ability of HIV to infect non dividing cells by facilitating the nuclear localization of the preintegration complex. (62) Vpr can also block cell division. (63)

Vpu:
HIV-2 does not contain vpu, but instead harbors another gene, vpx. The 16-kD Vpu polypeptide is an integral membrane phosphoprotein that is primarily localized in the internal membranes of the cell. (64) In HIV infected cells, complexes are formed between the viral receptor, CD4, and the viral envelope protein in the endoplasmic reticulum causing the trapping of both proteins to within this compartment. The formation of intracellular Env-CD4 complexes thus interferes with virion assembly. Vpu liberates the viral envelope by triggering the degradation of CD4 molecules complexed with Env. (65) Vpu also increases the release of HIV from the surface of an infected cell. (66)

Vif:
Vif is a 23-kD polypeptide that is essential for the replication of HIV in peripheral blood lymphocytes, macrophages, and certain cell lines.

The regulation of HIV gen expression

The regulation of HIV gene expression is accomplished by a combination of both cellular and viral factors. HIV gene expression is regulated at both the transcriptional and post-transcriptional levels. The HIV genes can be divided into the early genes and the late genes. The early genes, Tat, Rev, and Nef, are expressed in a Rev independent manner. The mRNAs encoding the late genes, Gag, Pol, Env, Vpr, Vpu, and Vif require Rev to be cytoplasmically localized and expressed. (39)

Clinical course of untreated HIV disease (8)

Primary infection

Transmission: (see Transmission)

Aborted HIV Infection

There is evidence that some individuals may successfully ward of infection after inoculation. Three somewhat different mechanisms are suggested by published reports:

• Defective co-receptor needed by HIV to infect cells
• Immune response capable of preventing HIV from establishing infection
• Mutation in the SDF-1 gene

• Spread of HIV to tissues and cells that ultimately may represent hard to eradicate viral reservoirs
• Extensive damage to lymph node cellular architecture
• Stimulation of an immune response against HIV
• Loss of HIV specific CD4+ and possibly CD8+ cell clones that may be effective in controlling HIV infection
• Rapid HIV replication and mutation creating a more genetically diverse population of HIV genomes, some perhaps more virulent, or more fit for replication in other micro environments such as in the presence of particular drugs or particular anti-HIV cytotoxic lymphocyte clones

CD4+ and CD8+ T cells are immunologically effective not just because of their numbers, as reflected in CD4+ and CD8+ T cell counts, but also because of their diversity. One factor probably determining ultimate disease progression is the extent of very early destruction of the subpopulation of CD4+ T cell clones capable of recognizing HIV antigens. Loss of these clones means loss of the CD4+ T cell component of the natural anti-HIV immune response, which is crucial in controlling HIV replication. (68)

Many, perhaps most, patients experience an acute syndrome within weeks of primary HIV infection and immune response. The syndrome commonly persists for several weeks. (69)

Following the HIV antibody rise, levels of detectable virus, HIV RNA, and viral antigens in peripheral blood drop dramatically. This lower range, which is called "set point", is relatively stable for months, perhaps years. Typically noted over this period is a drop in the CD4+ count, from normal levels to 200 to 300 cells/mm³. The frequently observed generalized lymphadenopathy syndrome is probably a manifestation of this process, although why lymphadenopathy is prominent only in some patients remains uncertain. (70) The baseline clinical state for many patients until late in the middle stage is minimal or no symptoms; other individuals, however, have subjective systemic symptoms, such as fatigue, and a few have fevers. Against the baseline of relative clinical wellness, common episodic conditions during these stages of disease include herpes zoster, thrush, seborrheic dermatitis, skin and nail infections and bacterial infections.

Advanced HIV Disease

Untreated patients with manifestations of advanced HIV disease typically have CD4+ counts below 200 cells/mm3, increased plasma HIV RNA levels, and clinical manifestations indicative of severe immunocompromise, including conditions qualifying as CDC-defined AIDS. Opportunistic infections commonly occur.

Late-Stage HIV Disease

As the disease advances further and the CD4+ count drops below 50 cells/mm3, additional opportunistic infections as well as central nervous system non-Hodgkin's lymphoma occur commonly, and, in homosexual males, existing kaposi's sarcoma may become extensive and cause disfigurement and clinically significant edema.

Death eventually results from extensive disease of vital organs, most commonly the lungs, and presumably from effects of circulating toxins, electrolyte abnormalities,
hematopoietic and circulatory failure, and autonomic nervous system damage.

Clinical manifestations of HIV Disease

Fever

The fever can last from a few days to longer than a month, with no other symptoms or disease present and no other obvious cause.

The Centers for Disease Control recognized wasting as an AIDS defining condition in 1987, defining the "wasting syndrome" as a weight loss of at least 10% in the presence of diarrhea or chronic weakness and documented fever for at least 30 days that is not attributable to a concurrent condition other than HIV infection itself. A significant relationship between weight loss and survival and/or disease progression has been demonstrated in numerous prospective and retrospective studies. Weight loss in HIV infection features depletion of both fat and lean tissue. Among the factors that have been demonstrated or hypothesized to contribute to wasting are metabolic alterations, anorexia, malabsorptive disorders, hypogonadism, and excessive cytokine production.

Oral manifestations of HIV disease are common and include oral lesions and novel presentations of previously known opportunistic diseases. (73)

HIV infected persons commonly have cutaneous abnormalities; the prevalence approaches 100%. (75) Some of the conditions are unique and virtually pathognomonic for HIV disease, for example, Kaposi’s sarcoma.

HIV is classified among the lentiviruses, a family of viruses characterized in part by their tendency to cause chronic neurologic disease in their animal hosts. Neurologic disease is the first manifestation of symptomatic HIV infection in roughly 10 to 20% of persons, while about 30 to 40% of patients with advanced HIV disease will have clinically evident neurologic dysfunction during the course of their illness. (77) The incidence of subclinical neurologic disease is even higher: autopsy studies of patients with advanced HIV disease have demonstrated pathologic abnormalities of the nervous system in 75 to 90% of cases. (77)

Entry into the central nervous system

The initial "seeding" of the nervous system by HIV-1 is usually asymptomatic, although acute aseptic meningitis, encephalitis, and inflammatory polyneuropathy have all occurred in this setting.

Pathogenesis of AIDS Dementia Complex (ADC)

The AIDS Dementia Complex (ADC) is one of the most common and clinically important central nervous system complications of late HIV-1 infection. It is a source of great morbidity and, when severe, is associated with limited survival. While its pathogenesis remains enigmatic in several important aspects, ADC is generally thought to be caused by HIV-1 itself, rather than to another opportunistic infection. (78) Although the severity and relative prominence of some symptoms and signs compared to others may vary among individual patients, the general character of ADC involves three functional categories: cognition, motor performance, and behavior. (79)

Cerebral symptoms and signs

Apart from dementia, HIV infected patients are at risk for a wide range of neurologic diseases. Cerebral signs and symptoms are the most common. Global cerebral disease can present with altered mental status or generalized seizures, while focal disease often produces hemiparesis, hemisensory loss, visual field cuts, or disturbances in language use.

Symptoms affecting cord, nerve roots and muscle

Below the foramen magnum, viral and, rarely, fungal and parasitic opportunistic infections can affect the spinal cord. Systemic lymphoma can infiltrate nerve roots and meninges, occasionally causing a mass lesion within the cord. In addition, HIV itself is associated with a spastic paraparesis similar to that seen with vitamin B12 deficiency.

Pain in AIDS

There is growing awareness that pain from a variety of etiologies commonly complicates HIV disease. In general, AIDS patients have pain comparable in prevalence and intensity to patients with cancer pain, with similar mixtures of neuropathic and visceral-somatic etiologies. However, while efforts to improve malignant pain management have benefited many cancer pain patients, pain in AIDS is dramatically undertreated.

Respiratory symptoms are a frequent complaint in HIV infected individuals. The Pulmonary Complications of HIV Infection Study demonstrated that respiratory symptoms are a frequent complaint in HIV infected individuals and increase in frequency as the CD4 cell count declines below 200. Respiratory symptoms may be due to a wide spectrum of pulmonary illnesses that includes both HIV and non-HIV related conditions. The HIV related conditions include both opportunistic infections and neoplasm's. The opportunistic infections include bacterial, mycobacterial, fungal, viral, and parasitic pathogens.

Since HIV disease was first recognized in 1981, case reports have described both clinical and autopsy evidence of cardiac abnormalities. The most obvious of these abnormalities has been pericarditis, at times with large effusions and often with cardiac tamponade. (82)

A number of endocrine abnormalities develop in patients with HIV infection, although many are likely to be nonspecific responses to infection, stress, and malnutrition. Others are due to infiltration of endocrine glands by tumor or infection.

Anemia is a very common finding in patients with HIV infection, particularly in individuals with more advanced HIV disease. Zidovudine  therapy is probably the most common cause of anemia in HIV infected patients.
Thrombocytopenia is also frequently associated with HIV infection.
Granulocytopenia is a problem commonly encountered in patients with HIV infection. Although low granulocyte counts usually reflect the toxicity of therapies for HIV infection (mostly zidovudine therapy) or associated conditions, studies of untreated patients have also shown a high incidence of granulocytopenia, particularly in patients with more profound immunodeficiency.

There is a broad spectrum of renal manifestations in human immunodeficiency virus infection , and these disorders are commonly encountered in patients in all stages of HIV infection. Although fluid and electrolyte disorders and acute renal failure are commonly found in hospitalized HIV infected patients, HIV associated nephropathy is the most clinically relevant and devastating renal disorder with patients progressing to end-stage renal disease rapidly. (86)

Gastrointestinal and hepatobiliary disorders are among the most frequent complaints of patients with HIV disease. Advances in antiretroviral therapy are changing the nature of HIV disease and affecting many of the gastrointestinal manifestations. Before combination antiretroviral therapy, the best estimates suggested that 50 to 93% of all patients with HIV disease had marked gastrointestinal symptoms during the course of their  illness. Recent clinical experience suggests that effective anti-HIV therapy and chemoprophylaxis may delay/prevent the occurrence of gastrointestinal opportunistic infections. Gastrointestinal manifestations of HIV disease include diarrhea, dysphagia and odynophagia, nausea, vomiting, weight loss, abdominal pain, anorectal disease, jaundice and hepatomegaly, gastrointestinal bleeding, interactions of HIV and hepatotropic viruses, and gastrointestinal tumors (Kaposi's sarcoma and non-Hodgkin's lymphoma).

Numerous ophthalmic manifestations of HIV infection may involve the anterior or posterior segment of the eye. Anterior segment findings include tumors of the periocular tissues and a variety of external infections. Posterior segment changes include an HIV-associated retinopathy and a number of opportunistic infections of the retina and choroid.

HIV disease is associated with a variety of problems in the head and neck region; as many as 70% of HIV infected patients eventually develop such conditions. The causes of most otolaryngologic manifestations of HIV disease fall into the following three categories: infections, neoplasm's, and primary neurologic damage caused by HIV. The infections of the head and neck are usually caused by the common expected pathogens in patients with a normal immune system, and the majority of patients respond to standard medical management. Unusual organisms, the pathogens frequently associated with HIV infection, have been isolated in the later stages of their disease. Kaposi's sarcoma and non-Hodgkin's lymphoma, the neoplasm's associated with HIV disease, can occur in the head and neck.

The patient with HIV infection is at risk for a wide spectrum of disease both common and exotic. To equally consider all of these processes in the differential diagnosis of any HIV infected patient can be overwhelming for the clinician and very expensive. HIV patients can be grouped into stages of HIV infection, AIDS itself representing only the very last stages of this infection. Using the CD4 count, patients can be generally grouped into four stages of HIV infection. When the CD4 count is over 500 cells/mm3, most patients are essentially asymptomatic. As the CD4 count drops to 200 to 500 cells/mm3, the early manifestations of HIV infection start to appear. As the CD4 count drops below 200 cells/mm3, patients become vulnerable to many of the processes associated with AIDS. As the CD4 count drops below 50 cells/mm3, patients become increasingly at risk for the unusual opportunistic infections highlighted in the medical literature. (89)

Infections

Malignancies

Three cancers are significantly more common among persons infected with HIV: Kaposi's sarcoma, non-Hodgkin's lymphoma , and Hodgkin's disease  In addition, there is epidemiologic evidence to suggest that cervical and anal dysplasia are associated with HIV. (90)