HIV1 Infection Leads to Opportunistic Infections

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Isolation of HIV-1 and its growth in culture has allowed purification of viral proteins and the development of tests for infection with the virus. The most commonly used test is for the presence of antibodies directed against proteins of HIV-1. These generally appear in the serum of infected individuals by three months after the infection has occurred. When the antibodies appear, the individual is said to have serocon-verted or to be seropositive for HIV-1. Although the precise course of HIV-1 infection and disease onset varies considerably in different patients, a general scheme for the progression of AIDS can be constructed (Figure 19-12). The course of HIV-1 infection begins with no detectable anti-HIV-1 an-

Seroconversion

Death

Seroconversion

Death

Seroconversion Images

Weeks

Years

FIGURE 19-12

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Weeks

Years

FIGURE 19-12

Serologic profile of HIV infection showing three stages in the infection process. Soon after infection, viral RNA is detectable in the serum. However, HIV infection is most commonly detected by the presence of anti-HIV antibodies after seroconversion, which normally occurs within a few months after infection. Clinical symptoms indicative of AIDS generally do not appear for at least 8 years after infection, but this interval is variable. The onset of clinical AIDS is usually signaled by a decrease in T-cell numbers and an increase in viral load. [Adapted from A. Fauci et al, 1996, Annals Int. Med. 124:654.]

tibodies or virus and progresses to the full AIDS syndrome. Diagnosis of AIDS includes evidence for infection with HIV-1 (presence of antibodies or virus in blood), greatly diminished numbers of CD4+ T cells (< 200 cells/mm3), impaired or absent delayed-hypersensitivity reactions, and the occurrence of opportunistic infections (Table 19-3). Patients with AIDS generally succumb to tuberculosis, pneumonia, severe wasting diarrhea, or various malignancies. The time between acquisition of the virus and death from the immunodeficiency averages nine to twelve years. In the period between infection and severe disease, there may be few symptoms. Primary infection in a minority of patients may be symptomatic with fever, lymphadenopathy (swollen lymph nodes), and a rash, but these symptoms generally do not persist more than a few weeks. Most commonly, primary infection goes unnoticed and is followed by a long chronic phase, during which the infected individual shows little or no overt sign of HIV-1 infection.

The first overt indication of AIDS may be opportunistic infection with the fungus Candida albicans, which causes the appearance of sores in the mouth (thrush) and, in women, a vulvovaginal yeast infection that does not respond to treatment. A persistent hacking cough caused by P. carinii infection of the lungs may also be an early indicator. A rise in the level of circulating HIV-1 (viral load) in the plasma and concomitant drop in the number of CD4+ T cells generally previews this first appearance of symptoms. Some relation between the CD4+ T-cell number and the type of infection experienced by the patient has been established (see Table 19-3). Of intense interest to immunologists are the events that take place between the initial confrontation with HIV-1 and the takeover and collapse of the host immune system. Understanding how the immune system holds HIV-1 in check during this chronic phase can lead to the design of effective therapeutic and preventive strategies.

Research into the process that underlies the progression of HIV infection to AIDS has revealed a dynamic interplay between the virus and the immune system. The initial infection event causes dissemination of virus to lymphoid organs and a resultant strong immune response. This response, which involves both antibody and cytotoxic CD8+ T lymphocytes, keeps viral replication in check; after the initial burst of viremia (high levels of virus in the circulation), the viral level in the circulation achieves a steady state. Although the infected individual normally has no clinical signs of disease at this stage, viral replication continues and virus can be detected in circulation by sensitive PCR assays for viral RNA. These PCR-based assays, which measure viral load (the number of copies of viral genome in the plasma), have assumed a major role in determination of the patient's status and prognosis. Even when the level of virus in the circulation is stable, large amounts of virus are produced in infected CD4+ T cells; as many as 109 virions are released every day and continually infect and destroy additional host T cells (Figure 19-13a). Despite this high rate of replication, the virus is kept in check by the immune system throughout the

TABLE 19-3 Clinical diagnosis of HIV-infected individuals

CLINICAL CATEGORIES*

CLASSIFICATION OF AIDS INDICATOR DISEASE

Category A

Asymptomatic: no symptoms at the time of HIV infection

Acute primary infection: glandular fever-like illness lasting a few weeks at the time of infection

Persistent generalized lymphadenopathy (PGL): lymph-node enlargement persisting for 3 or more months with no evidence of infection

Category B

Bacillary angiomatosis

Candidiasis, oropharyngeal (thrush)

Candidiasis, vulvovaginal: persistent, frequent, or poorly responsive to therapy

Cervical dysplasia (moderate or severe)/cervical carcinoma in situ

Constitutional symptoms such as fever (> 38.5°C) or diarrhea lasting > 1 month

Hairy leukoplakia, oral

Herpes zoster (shingles) involving at least two distinct episodes or more than one dermatome

Idiopathic thrombocytopenic purpura

Listeriosis

Pelvic inflammatory disease, particularly by tubo-ovarian abscess

Peripheral neuropathy

Category C Candidiasis of bronchi, tracheae, or lungs Candidiasis, esophageal Cervical cancer (invasive)

Coccidioidomycosis, disseminated or extrapulmonary Cryptococcosis, extrapulmonary

Cryptosporidiosis, chronic intestinal (> 1 month duration) Cytomegalovirus disease (other than liver, spleen, or nodes) Cytomegalovirus retinitis (with loss of vision) Encephalopathy, HIV-related

Herpes simplex: chronic ulcer(s) (> 1 month duration), bronchitis, pneumonitis, or esophagitis

Histoplasmosis, disseminated or extrapulmonary

Isosporiasis, chronic intestinal (> 1 month duration)

Kaposi's sarcoma

Lymphoma, Burkitt's

Lymphoma, immunoblastic

Lymphoma, primary of brain

Mycobacterium avium complex or M. Kansasii, disseminated or extrapulmonary

Mycobacterium tuberculosis, any site

Mycobacterium, other or unidentified species, disseminated or extrapulmonary

Pneumocystis carinii pneumonia

Progressive multifocal leukoencephalopathy

Salmonella septicemia (recurrent)

Toxoplasmosis of brain

Wasting syndrome due to HIV

*All categories shown in bold type are considered AIDS. For Category A diagnosis, no condition in categories B or C can be present; for category B, no category C condition can be present.

SOURCE: CDC guidelines for AIDS diagnosis, 1993 revision.

chronic phase of infection, and the level of virus in circulation from about six months after infection is a good predictor of the course of disease. Low levels of virus in this period correlate with a longer time in which the infected individual remains free of opportunistic infection. But the virus eventually breaks through host immune defenses, resulting in an in crease in viral load, a decrease in CD4+ T cell numbers, increased opportunistic infection, and death of the patient.

While the viral load in plasma remains fairly stable throughout the period of chronic HIV infection, examination of the lymph nodes has revealed a different story. Fragments of nodes obtained by biopsy from infected subjects

HIV-infected CD4+ T cell

Dead cell

HIV-infected CD4+ T cell

Dead cell

(a) HIV-infected CD4+ T cell releases HIV virus; some virus infects other CD4+ T cells, some is rapidly neutralized by immune mechanisms

Chain Infection

Anti-retroviral therapy inhibits viral production.

Cycle of virus infection and production, and death of CD4+ T cells continues at a steady-state level

CD4+ T-cell number increases

(a) HIV-infected CD4+ T cell releases HIV virus; some virus infects other CD4+ T cells, some is rapidly neutralized by immune mechanisms

Anti-retroviral therapy inhibits viral production.

Cycle of virus infection and production, and death of CD4+ T cells continues at a steady-state level

CD4+ T-cell number increases

FIGURE 19-13

Production of virus by CD4 T cells and maintenance of a steady state of viral load and T-cell number. (a) A dynamic relationship exists between the number of CD4+ cells and the amount of virus produced. As virus is produced, new CD4+ cells are infected, and these infected cells have a half-life of 1.5 days. In progression to full AIDS, the viral load increases and the CD4+ T-cell count decreases before onset of opportunistic infections. (b) If the viral load is decreased by anti-retrovi-ral treatment, the CD4+ T-cell number increases almost immediately.

showed high levels of infected cells at all stages of infection; in many cases, the structure of the lymph node had been completely destroyed by virus long before plasma viral load increased above the steady-state level.

The decrease in CD4+ T cells is the hallmark of AIDS. Several explanations have been advanced for the depletion of these cells in patients. In early studies, direct viral infection and destruction of CD4+ T cells was discounted as the primary cause, because the large numbers of circulating HIV-infected T cells predicted by the model were not found. More recent studies indicate that the reason for the difficulty in finding the infected cells is that they are so rapidly killed by HIV; the half-life of an actively infected CD4+ T cell is less than 1.5 days. There are smaller numbers of CD4+ T cells that become infected but do not actively replicate virus. These latently infected cells persist for long periods, and the integrated proviral DNA replicates in cell division along with cell DNA. Studies in which viral load is decreased by anti-retroviral therapy show a concurrent increase in CD4+ T cell numbers (Figure 19-13b). These data support a model of dynamic interaction between virus and T cells, with simultaneous high levels of viral production and rapid depletion of infected CD4+ T cells. While other mechanisms for depletion of CD4+ T cells may be envisioned, infection with HIV remains the prime suspect.

Not only depletion of CD4+ T cells but other immuno-logic consequences can be measured in HIV-infected individuals during the progression to AIDS. These include a decrease or absence of delayed hypersensitivity to antigens to which the individual normally reacts. Serum levels of im-munoglobulins, especially IgG and IgA, show a sharp increase in the AIDS patient. This increase may be due to increased levels in HIV-infected individuals of a B-cell subpopulation with low CD21 expression and enhanced im-munoglobulin secretion. This population proliferates poorly in response to B-cell mitogens. Cellular parameters of im-munologic response, such as the proliferative response to mi-togens, to antigens, or to alloantigens, all show a marked decrease. Generally, the HIV-infected individual loses the ability to mount T-cell responses in a predictable sequence: responses to specific antigens (for example, influenza virus) are first lost, then response to alloantigens declines, and lastly, the response to mitogens such as concanavalin A or phytohemagglutinin can no longer be detected. Table 19-4 lists some immune abnormalities in AIDS.

HIV-1 infected individuals often display dysfunction of the central and peripheral nervous systems. Specific viral DNA and RNA sequences have been detected by HIV-1 probes in the brains of children and adults with AIDS, suggesting that viral replication occurs there. Quantitative comparison of speci-

TABLE 19-41 Immunologic abnormalities associated with HIV infection

Stage of infection Typical abnormalities observed

LYMPH NODE STRUCTURE

Early Infection and destruction of dendritic cells; some structural disruption

Late Extensive damage and tissue necrosis; loss of folicular dendritic cells and germinal centers; inability to trap antigens or support activation of T and B cells

T HELPER (Th) CELLS

Early No in vitro proliferative response to specific antigen

Late Decrease in TH-cell numbers and corresponding helper activities; no response to T-cell mitogens or alloantigens

ANTIBODY PRODUCTION

Early Enhanced nonspecific IgG and IgA production but reduced IgM synthesis

Late No proliferation of B cells specific for HIV-1: no detectable anti-HIV antibodies in some patients; increased numbers of

B cells with low CD21 and enhanced Ig secretion.

CYTOKINE PRODUCTION

Early Increased levels of some cytokines

Late Shift in cytokine production from TH1 subset to TH2 subset

DELAYED-TYPE HYPERSENSITIVITY

Early Highly significant reduction in proliferative capacity of Tdth cells and reduction in skin-test reactivity

Late Elimination of DTH response; complete absence of skin-test reactivity

T CYTOTOXIC (TC) CELLS

Early Normal reactivity

Late Reduction but not elimination of CTL activity due to impaired ability to generate CTLs from TC cells mens from brain, lymph node, spleen, and lung of AIDS patients with progressive encephalopathy indicated that the brain was heavily infected. A frequent complication in later stages of HIV infection is AIDS dementia complex, a neurological syndrome characterized by abnormalities in cognition, motor performance, and behavior. Whether AIDS dementia and other clinical and histopathological effects observed in the central nervous systems of HIV-infected individuals are a direct effect of viral antigens on the brain, a consequence of immune responses to the virus, or a result of infection by opportunistic agents remains unknown.

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Responses

  • LYNN
    Why HIV infection leads to opportunistic infection?
    2 years ago
  • milen
    How many stages are there in the chain of infection?
    2 years ago

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