HIV replication

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HIV can infect T4 lymphocytes and other cells bearing the CD4 marker on their surface. The CD4 molecule is the main receptor for HIV, or more precisely for its gp120 (Fig. 8.14). In addition, either the chemokine receptor CCR5 (macro-phage-tropic R5 HIV strains) or CXCR4 (T cell-tropic X4 strains) is used as a core-ceptor. Persons with (homozygotic) missing CCR5 are highly resistant to HIV infection. A number of other coreceptors are also active depending on the viral strain involved. HIV is then taken in by the cell. After uncoating, reverse transcription takes place in the cytoplasm. The rest of the viral replication process basically corresponds to the description of retroviral replication on p. 385. The interaction of the many different contributing control genes is responsible for the long latency period and subsequent viral replication (see also Fig. 8.14).

Replication of HIV takes the form of a lytic cycle, i.e., it results in destruction of the host cell, making it an exception among retroviruses. It must also be noted that the cell destruction mechanism has not been completely explained. Cell fusions are induced by X4 strains (syncytial formation). These processes occur late in the infection cycle and are associated with progression to AIDS. R5 strains do not induce syncytia, are present early in the course of the infection, and are mainly responsible for transmission of HIV. Besides virus-induced cell destruction (p. 392), apoptosis also appears to play an important role in the elimination of CD4+ cells.

Pathogenesis and clinical picture. AIDS was described as a discrete pathology of the immune system in 1981. The pathogenicity of the disease is based on suppression of cellular immunity as a result of the loss of the CD4+ T helper cells. 8

The primary infection either remains inapparent or manifests as "acute retroviral syndrome" with conjunctivitis, pharyngitis, exanthem, and lymph-adenopathy, as well as a transitory meningoencephalitis in some cases. p24 antigen (Fig. 8.14) is detectable in serum after about 14 days, i.e., before the antibodies. This stage is followed by a long period of clinical latency (the incubation period is described as 10 years), during which the carrier is clinically normal but may be infectious. The HI virus can persist in a latent state in CD4+ T lymphocytes, macrophages, and the Langerhans cells in the skin. Apparently, viral replication continues throughout this period, especially in lym-phoid organs.

The drop in CD4+ lymphocytes and the rise in the virus count (viral load, see below) in peripheral blood is followed by the lymphadenopathic stage. Opportunistic infections then set in, frequently combined with lymphomas, the otherwise rare Kaposi sarcoma, or so-called AIDS encephalopathy (sub-acute AIDS encephalitis, AIDS dementia complex). Similar neurological symptoms may also be induced because of HIV-induced immunosuppression,

Table 8.4 Diagnostic Definitions for AIDS in Adults

Clinical categories B

>500

200-499

<200

A3, B3, and C1-3 confirm AIDS diagnosis Clinical categories

A: Asymptomatic or acute (primary) HIV infection; persistent generalized lymphade-nopathy (LAS)

B: Symptoms indicative of weakened cellular immune defenses, but no AIDS-defining diseases.

C: AIDS-defining diseases: Viruses

HSV: chronic ulcer, esophagitis, bronchitis, pneumonia

VZV: generalized zoster

CMV: retinitis, encephalitis, pneumonia, colitis

JC virus: progressive multifocal leukoencephalopathy

HIV: encephalitis

HIV: wasting syndrome

8 Bacteria

Recurrent salmonellar septicemia Recurrent pneumonia

Mycobacterial tuberculosis, pulmonary and extrapulmonary forms Opportunistic mycobacteria (M. avium, etc.), disseminated or extrapulmonary

Protozoans

Cryptosporidium: chronic diarrhea Isospora belli: chronic diarrhea Toxoplasma gondii: encephalitis

Fungi

Candida: esophagitis, pneumonia, bronchitis

Histoplasma, Cryptococcus neoformans, coccidiosis: extrapulmonary, disseminated Pneumocystis carinii: pneumonia

Malignomas Kaposi sarcoma Invasive cervical carcinoma B-cell lymphoma EBV-positive

Toxoplasma or papovaviruses (PML, see p. 415), or lymphomas. Table 8.4 presents the CDC (Centers for Disease Control) classification of the stages in the course of HIV infection. The number of CD4+ T cells and the occurrence of so-called AIDS-defining diseases determine whether an HIV-positive patient is categorized as a case of AIDS (Table 8.4). The probability that an AIDS-defining disease will occur rises precipitously at CD4+ cell counts below 200.

Laboratory diagnosis. The following diagnostic tools are currently available for confirmation of an HIV infection (not the same as manifest AIDS, see above):

■ HIV antibody detection. EIA screening tests are now available using genetically engineered or synthesized viral antigens (first to third generation of screening tests). Every positive result requires confirmation by an alternative test (Western blot, see p. 123 and Fig. 2.24, p. 125, p24 antigen detection). The fourth-generation screening tests simultaneously detect antibodies to HIV 1 and 2 and p24 antigen (combination test) and are thus capable of detecting primary infections that are still antibody-negative.

■ HIV antigen detection. In this test, a viral protein is detected in serum, usually capsid protein p24. The p24 antigen is detectable in serum as early as two weeks after infection and disappears again after eight to 12 weeks. Following a clinically stable latency period, HIV antigen can become detectable months or years later (transitory or persistent). This renewed appearance of HIV antigen is usually followed by manifest AIDS and is therefore a negative prognostic sign.

■ Rapid HIV test. Antibody-based tests are available for rapid diagnosis in medical practices, hospitals, and health centers. Their specifications are 8 equivalent to the third-generation screening tests.

■ PCR. The most important application of the polymerase chain reaction (PCR, see p. 409) today is to determine the so-called viral load, whereby a commercially available quantitative RT-PCR (reverse transcriptase PCR) is used to determine the number of viral RNA molecules per ml of blood, taking into account the added standard amounts of HIV RNA (quantification standard). This test provides a prognostic estimate of how great the risk of progression to AIDS is (manifestation of an AIDS-defining disease). It can also be used to monitor the success of therapy with RT and protease inhibitors.

The following HIV diagnostic procedure is now recommended: an HIV antibody screening test should first be performed to diagnose an HIV infection. If the test result is positive, a second serum specimen should be tested to confirm the result and exclude confusion of sera. If the initial screening test is negative, but a (primary) HIV infection is justifiably suspected, HIV antigen can be tested, for instance using the combination test.

Epidemiology and prevention. HIV is transmitted by blood, blood products, and sexual intercourse. The virus can also be transmitted from mother to child in intrauterine infection, perinatal transmission, or the mother's milk. Infection via saliva or insect bite has not been confirmed. Accordingly, three rules of behavior are now propagated to prevent the spread of HIV: use a good-quality condom for each act of sexual intercourse. For i.v. drug consumption use only sterile syringes and needles; never share or pass on these injection utensils. Couples one of whom is HIV-positive should avoid an unplanned pregnancy.

Intensive efforts are being made to develop a vaccine (active immunization) and several vaccines will soon be ready for field trials. The types under consideration include split vaccines (p. 403), genome-free particles, attenuated viruses, naked DNA, and inactivated virions. It is not practicable to cover this field of research in detail here due to the fast-moving, and the necessarily tenuous, nature of the ongoing work.

Therapy. The recommended therapeutic procedure is also subject to rapid changes, whereby the common goal is to reduce the number of viruses as far as possible (<50 RNA copies per ml) and as soon as possible. Doing so can delay the occurrence of clinical symptoms, eliminate existing symptoms and slow or stop the development of resistance in the HI viruses.

In general, therapy is considered in reaction to the initial retroviral syndrome. Therapy is recommended in the first, asymptomatic stage at CD4+ cell counts below 350, and if the count is higher than 350 only if the viral load is raised (consider therapy at 5000, therapy recommended at >30 000 RNA copies/ml). Pregnancy in an HIV-positive woman is a further therapeutic indication.

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