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AIDS (Acquired Immune Deficiency Syndrome) is the end stage of a long-term pathogenic process in which the immune system of an infected person and its ability to control infections or malignant proliferative disorders are progressively destroyed. (Clinical, p.513) It is characterized by a gradual decrease of CD4+ T lymphocytes from blood, which correlates with reducing the immune competency. (8) The causative agents of AIDS are HIV-1, identified in 1983, and HIV-2, identified in 1986, which are members of the genus Lentivirinae in the Retroviridae family. HIV-1 is more aggressive virus and is responsible for the AIDS pandemic, while HIV-2 is much less pathogenic than HIV-1, and only endemic in West Africa. (Clinical, p.513) Until now, it is still not clear how much of the pathogenesis of AIDS is due to the virus and how much is caused by the immune system itself (23), but some mechanism of the development of AIDS have been proposed, such as apoptosis. Not only are all AIDS patients found to be infected with HIV, but most HIV-infected persons eventually develop AIDS. (Medical, p.548)
Properties of Human Immunodeficiency Viruses
The HIV virion is an enveloped virus and with a dense core appears cone-shaped. In the envelope, it contains a glycoprotein antigen gp160, which have been cleaved into two components, gp120 and gp41. gp120 molecule is the most extensively glycosylated viral protein known, and it is presumed that it is a protective device to impede access of neutralizing antibodies. gp41 molecule, which is responsible for viral entry into the host cell by membrane fusion. The inner surface of the envelope is linked by protein, p17, a product of gag gene (standing for group-specific antigen) product. The most abundant vial protein is the phosphoprotein p24, of which the icosahedral nucleocapsid is constructed; the other two are p9 and p7, which are closely associated with the genome in the core of the virion. Also, associated with the genome in the core are three viral enzymes: reverse transcriptase, endonuclease, and protease. Two types of HIV are currently recognized. HIV-2 displays only about 40-50% nucleotide sequence homology with HIV-1 and contains a unique gene, vpx, while vpu gene is only found in HIV-1 genome. (Medical, p.539-541)
Moreover, HIV exhibits extensive heterogeneities. It is because the viral RT (reverse transcriptase) is very error prone and thus appears to give rise readily to changes in the genome. Currently, based on full-length viral genome sequencing, there are three HIV-1 groups called M (main), O (outlier), and N (non M or O). Eight HIV-2 groups have been identified (groups A to H). Within the M group, nine HIV-1 subtypes have been recognized, they are designated A to D, F to H, J and K, some subtypes have been distinguished for group O, but only a few isolates of group N have been identified. No subtypes of the HIV-2 groups have yet been identified. Each HIV-1 subtype differs from the others in amino acid composition by at least 20% in the env region and 15% in the gag region. The distribution of the various subtypes of HIV is unevenly throughout the world. (HIV, p.13-14) On the other hand, dualtropism is also the properties of HIV. R5 and X4 viral phenotypes have been proposed. The different biologic characteristics of R5 and X4 phenotypes can be distinguished by the chemokine co-receptors involved (R5 phenotype associated with CCR5, while X4 phenotype associated with CXCR4); and its cytopathicity, in which X4 phenotype has SI (syncytium induction) property, but R4 phenotype is NSI (non-syncytium induction). (HIV, p.62, 133)
HIV infection and its pathogenesis
HIV is transmitted by unprotected sexual intercourse, from mother to child, by breast feeding, and by parenteral inoculation. (Clinical, p.520) The cells to become infected may be resident tissue macrophages or submucosal lymphocytes in the genital tract or rectum, but the virus is then transported to the draining lymph nodes, where it replicates extensively. One to three weeks after infection, most patients exhibit a brief glandular fever-like illness, associated with a high titer of virus in the blood and a decline in CD4+ T cells. A vigorous cellular and humoral immune response ensues, and within a month or so the viraemia declines to a near undetectable level. CD8+ cytotoxic T cells, natural killer (NK) cells, and antibody-dependent cell-mediated cytotoxicity (ADCC) may all contribute to this decline by lysing infected cells, while antibodies neutralizing free virions. (Medical, p.544)
After that, it follows a long asymptomatic period of clinical latency, lasting from about 1 to 15 years or longer, before any further clinical evidence of disease becomes apparent. During this period, only very low titers of virus in blood, and only a minority of circulating CD4+ T cells are producing virus. However, much higher levels of virus are detectable in lymph nodes. As time passes there is a steady decline in the number of CD4+ T cells. When CD4+ cell counts fall below about 200-400 per μL, opportunistic infections may occur, and eventually the depleted immune system is unable to cope. HIV infection can be directly cytolytic for activated CD4+ T cells, or can cause them to fuse with uninfected CD4+ cells to form a labile syncytium. Second, infected T cells are subject to immune cytolysis by cytotoxic T lymphocytes, ADCC, or antibody / complement-mediated lysis. Third, as a result of cross-linking of CD4 by HIV gp120, or by other mechanisms, T cells may be activated to commit suicide by apoptosis (programmed cell death). However, dying CD4+ T cells are not totally replenished, it has been postulated that HIV might also infect stem cells, or other cells that normally secrete cytokines required for such replacement. Moreover, early in the asymptomatic phase, HIV preferentially destroys memory CD4+ T cells. (Medical, p.546)
The pathogenic pathway, after the acute infection period, can be divided into three major phases. In the first phase, the reduction in CD4+ cell number and immune function reflects a common effect of viral infection, but then with HIV these parameters continue to decrease in association with the slow but persistent replication of relatively noncytopathic, usually macrophage-tropic R5 viruses (phase 2). The viruses reduce the CD4+ cell number either by direct cytotoxicity or , more often, by an indirect means such as apoptosis. When the CD4+ cell number is decreased to a level too low to support strong cell-mediated immunity, CD8+ cell anti-HIV acitivity becomes compromised. HIV replication then returns to its high levels, which is the third major phase of pathogenesis. At this time, a more virulent X4 cytopathic strain often emerges that is associated with the ultimate demise of the host. (HIV, p.324)
In the terminal stage, CD8+ cells, as well as CD4+ cells, decrease in number because of the loss of IL-2 production by CD4+ cells. Apoptosis of both cell types can also be involved. Included in this pathogenic pathway is the disruption in the normal immune balance reflected in lymph node structure and bone marrow integrity, often associated with development of severe opportunistic infections and malignancies. Moreover, the possibility that cytokine production and hyperresponsiveness of the immune system (e.g. autoimmunity and immune activation) also contribute to the final outcome needs to be considered.
Early period following acute virus infection (Phase 1)
The virus initially enters the body by infecting CD4+ cells, resident macrophages, dendritic cells, or mucosal cells lining the rectal or cervicovaginal cavity. With subsequent transit into the blood, the first cells infected are most probably tissue DCs and macrophages (particularly in lymph nodes or spleen) that are in a differentiated state ready to replicate the virus. These cells then pass virus to T cells after lymphocyte activation. Once the virus infection goes from the initial site to local lymph nodes (within 2 days), the infection has become established. Viremia results in 5 to 7 days with up to >107 viral RNA molecules per ml of plasma detected. After 10-14 days, up to 200 billion CD4+ cells can be infected.
In acute infection, the CD8+ cell numbers rise, also production of cytokines occurs, and bringing more target cells to the mucosal site of infection. It is , therefore, during this early period, before a sufficient antiviral response develops large numbers of cells become infected in lymphoid tissues. The replicating virus can undergo mutations that increase its virulence.
Generally, within weeks after acute infection, viremia is reduced substantially, considered by many as a result of the immune response against HIV. It is suggested that this decrease in virus could also reflect a loss of target cells. In the lymph node as well as in the blood at this time, only a small percentage of infected cells (<1%) actively produce virus.
Seroconversion takes place within days to weeks after infection but neutralizing antibodies appear to be present only transiently. During the acute or early period, before strong anti-HIV immune responses occur, the viremia reflects replication of a predominant HIV strain detected as relatively homogeneous virus population.
Persistent period (Phase 2)
At 3 to 6 months after primary virus infection, CD4+ cell numbers usually return to near-normal levels. They then generally decrease steadily. During this asymptomatic period (i.e., phase 2) with virus persistence, HIV replication in the body continues but generally at a low level, particularly in lymph nodes. This virus population becomes heterogeneous, i.e. emergence of different virus variants. Only 1 in 300 to 400 infected cells in the lymph node may release infectious virus. Peripheral blood contains, in 1 ml, about 1 to 100 IP and 1 to 100000 infected cells. This continued suppression of HIV replicating during the persistent period appears to be mediated by antiviral C84+ cells that help prevent the emergence of a virulent virus.
Symptomatic period (Phase 3)
Within 10 years after infection, many infected individuals develop symptoms, CD4+ cell counts have usually dropped below 350 cells/μl, viral load increases substantially, and a reduction in antiviral CD8+ cell responses can be demonstrated. The lack of CD8+ cell suppressing activity is probably reflected in the increased expression of HIV mRNA in CD4+ cells that is detected up to 2 years before the development of disease. This event presages the development of AIDS. The change in the clinical course appears to be directly related to a reduced cellular immune response, particularly CD8+ cell antiviral activity.
During this symptomatic period, when the individual develops AIDS, the amount of HIV rises to high levels in the blood and lymph node3 and once again becomes relatively homogeneous. As observed in primary infection, when antiviral immune responses are absent or low, a predominant virus strain emerges. This virus (often with the X4 phenotype) has properties associated with virulence in the host that include rapid replication and CD4+ cell cytopathicity. This virus is usually related to the early virus at the genomic level (>97%), but certain genetic changes in the regulatory (e.g., tat), enevelop, and pol regions.
In end-stage disease, CD4+ T cells, rather than macrophages, are still the major source of virus. Lower expression of CXCR4 and high expression of CCR5 have been found on CD4+ T cells in patients progressing to disease.
Suppression of HIV replication in the host is the most important factor in preventing the progression to disease. Both inhibition of non-cytopathic strains and suppression of more virulent viruses depended on strong antiviral cell-mediated immune responses. Sufficient functioning of both CD4+ and CD8+ cells is needed to control HIV pathogenesis. In the case of the CD8+ cell non-cyctotoxic response, the loss of IL-2 or CD8+ cell antiviral factor (CAF) production could lead to the release of virus from its latent state and advancement to disease.
In summary, the steps involved to HIV infection and progression to disease are multifactorial. The common host factor influencing delay in disease progression is the inherited genetic makeup of the individual, which can determine both the susceptibility of cells to HIV replication and the effectiveness of the antiviral cellular immune response. (HIV, p.326-332)
How an individual is confirmed to be HIV positive
HIV infection can be detected by a variety of tests. Virus can be directly detected by assays for the various virus components, for examples, the core protein p24, which can be specifically assayed by immunological tests. However, most frequently, HIV infection is diagnosed by tests that assess whether an individual's immune system has produced an HIV-specific immune response, so testing for HIV-specific antibodies is the main tool for the diagnosis of HIV. Nowadays, diagnosis of HIV infection relies on commercially available test kits, those products are well standardized with high sensitivity and specificity. (Clinical, p.525)
Since HIV-specific antibodies are produced within a few weeks after infection. The time to positivity (i.e., to seroconversion) in antibody tests may depend on the virus, the infectious dose, the transmission mode, and the sensitivity of the antibody assay. The standard test for HIV infection screening is the EIA (enzyme immunoassay) and the updated format used are called double-antigen sandwich assay (also called 3rd generation assay). This test uses antigens coated on wells or beads, it acts as target for patient's corresponding antibody, so that bound antibody is detected with the same labeled antigens added in solution. (Clinical, p.527) More recently, combined tests that detect both antibodies (antibodies to HIV-1 and HIV-2), and core antigen p24 are now available in commercial, such as Biomerieux VIDAS HIV Duo (HIV6). This may be referred as 4th generation assay. Other rapid test, such as SD Bioline for HIV can yield results within 30 minutes. Such tests may be useful in assessing the risk of HIV transmission in needle stick injuries, in organ donations, and use as repetitions of positive result. However, in order to act as a screening test, the selected kits should be at least detect antibodies to both HIV-1 and HIV-2, and have a good sensitivity to group M and O infections, and perform well in seroconversion panels. Positive samples or those with results in a borderline zone must be retested and, if repeatedly positive, a confirmatory test such as Western blot must be performed to validate the results. (Clinical, p.525) Moreover, HIV infection must never be established on a single sample, even if reactivity in screening has been confirmed by at least one supplemental test. Samples reactive in a screening test should be retested in a second, different screening assay, and performed in different runs. This reduces the possibility of human errors, such as sample mix-up or contamination which might lead to a false-positive diagnosis. (Clinical, p.537)
In order to confirm positive EIA results of HIV, further test should be performed. The most widely used method is Western blot. In this method, individual antigens of HIV are electrophoretically separated according to size into bands, the viral protein are then transferred onto test strips of nitrocellulose paper and then reacted with patient's serum. Any HIV antibody from the patient's serum is detected by antihuman IgG antibody conjugated with an enzyme that in the presence of substrate will produce a coloured band. A positive test result for HIV-1 is defined by the presence of any two of the following bands from HIV-1 gene products p24, gp41, or gp120 with absence of HIV-2 peptide band (the HIV-2 env glycoproteins are gp40, gp105 and gp130). (18) While positive test result for HIV-2 is defined by the presence of HIV-2 peptide band and any bands from gene products of p24 or gp41, and absence of gp120 band. However, if fewer bands are present only, the test is considered indeterminate. Patients with indeterminate assay of Western blot should be repeat testing or testing by other methods, such as PCR or viral culture. To issue a final report of HIV positivity, both positive results of EIA and Western blot are necessary. This combination assay have a sensitivity and specificity above 99%. (18)
Tests for viral RNA or DNA
There are three different techniques for the detection of HIV RNA or DNA: PCR (polymerase chain reaction), NASBA (nucleic acid sequence based amplification) and bDNA (branch-DNA) method. In PCR, cDNA must first be generated by reverse transcription. This cDNA can then be amplified and analyzed by ELISA. In NASBA, RNA is amplified and the procedure mimics the retroviral nucleic acid replication cycle. While in bDNA method, viral RNA is captured on a solid surface. The captured RNA is then hybridize with one end to a series of short sequences of the pol region of the RNA and with the other end mediate fixation of bDNA detector probes. These bDNAs are then reacted with still other bDNAs that hybridize to the first. Enzyme-labelled tracer probes are finally hybridized to all the branches, and the analysis is based on chemiluminescence. bDNA is therefore called signal amplification. The above mentioned nucleic acid detection technologies are primarily designed for the quantification of viral RNA. (Clinical, p.533)
Diagnosis of pediatric HIV infection
30-50% of babies born to mothers infected with HIV will be infected. Determining whether a newborn is infected with HIV by antibody tests is hindered by the fact that maternal IgG antibody crosses the placenta and does not disappear for 6-15 months. (Lab, p.489) The acquired maternal IgG against HIV is indistinguishable from antibody produced by the infant. Thus, virtually all infants born to HIV-infected mother will have detectable antibodies to HIV. (18) In addition, infants who are infected with HIV are immunosuppressed and may not develop a detectable antibody response to the virus at any time in their lives. (Lab, p.489) Therefore, there are only three methods to diagnose of HIV infection in babies. This includes detection of HIV p24 antigen, virus culture and PCR. (18)
Undoubtedly, infection of HIV is necessary for the development of AIDS, so a better understanding of the pathogenesis of AIDS and also the role of the immune system in the early stages of the disease is important to allow the development of more appropriate therapies for AIDS. Combination treatment such as highly active antiretroviral therapy (HAART) may result in sustained reduction of the plasma viral RNA below the detection limit and temporarily restores CD4+ cell count. Although, infection with HIV appears to be lifelong and AIDS is still an incurable disease, through increasing knowledge of the virus and our immune response to the virus, together with improved treatments for other opportunistic infections, and antiretroviral therapy early in the course of HIV disease can lengthen the life expectancy of persons infected with HIV.