Natural History of HIV Infection

The course of HIV infection can be best understood in terms of an interplay between HIV and the immune system. Three phases reflecting the dynamics of virus-host interaction can be

recognized: (1) an acute retroviral syndrome; (2) a middle, chronic phase; and (3) full-blown AIDS (see Fig. 6-45 ; also Fig. 6-50 ). [141] We first present the cardinal features of the phases

of HIV infection and their associated clinical syndromes then recount the sequential virologic and immunologic findings during the course of HIV infection.

The acute retroviral syndrome represents the initial or primary response of an immunocompetent adult to HIV infection. [142] It is characterized initially by a high level of virus production,

viremia, and widespread seeding of the lymphoid tissues. The initial infection, however, is readily controlled by the development of an antiviral immune response. It is estimated that 40%

to 90% of individuals who acquire a primary infection develop the viral syndrome 3 to 6 weeks after infection, and this resolves spontaneously in 2 to 4 weeks. Clinically, this phase is

associated with a self-limited acute illness with nonspecific symptoms, including sore throat, myalgias, fever, rash, weight loss, and fatigue, resembling a flulike syndrome. Other clinical

features, such as rash, cervical adenopathy, diarrhea, and vomiting, may also occur.

The middle chronic phase represents a stage of relative containment of the virus, associated with a period of clinical latency. The immune system is largely intact, but there is continuous

HIV replication, predominantly in the lymphoid tissues, which may last for several years. Patients are either asymptomatic or develop persistent generalized lymphadenopathy. In addition,

many patients have minor opportunistic infections, such as thrush and herpes zoster. Thrombocytopenia may also be noted ( Chapter 13 ). Persistent lymphadenopathy with significant

constitutional symptoms (fever, rash, fatigue) reflects the onset of immune system decompensation, escalation of viral replication, and onset of the crisis phase.

The final phase is progression to AIDS. It is characterized by a breakdown of host defense, a dramatic increase in plasma virus, and clinical disease. Typically the patient presents with longlasting

fever (>1 month), fatigue, weight loss, and diarrhea. After a variable period, serious opportunistic infections, secondary neoplasms, or clinical neurologic disease (grouped under the

rubric AIDS indicator diseases, discussed below) supervene, and the patient is said to have developed AIDS.

In the absence of treatment, most but not all patients with HIV infection progress to AIDS after a chronic phase lasting from 7 to 10 years. Exceptions to this typical course are exemplified

by long-term nonprogressors and by rapid progressors. Nonprogressors are defined as untreated HIV-1-infected individuals who remain asymptomatic for 10 years or more, with stable CD4

+ counts and low levels of plasma viremia. In rapid progressors, the middle, chronic phase is telescoped to 2 to 3 years after primary infection. The possible basis for these variant

outcomes is discussed later.

With this overview of the phases of HIV disease, we can consider some details of host-parasite relationships during the course of a typical HIV infection. The initial entry of the virus may

be through a mucosal surface, as in sexual intercourse (via rectal or cervical mucosa) or via blood exposure (e.g., after intravenous drug use). From the mucosal portal, the virus is carried

to the regional lymph nodes by dendritic cells.

Figure 6-50Typical course of HIV infection. A, During the early period after primary infection, there is widespread dissemination of virus and a sharp decrease in the number of CD4+ T

cells in peripheral blood. An immune response to HIV ensues, with a decrease in viremia followed by a prolonged period of clinical latency. During this period, viral replication continues.

The CD4+ T-cell count gradually decreases during the following years, until it reaches a critical level below which there is a substantial risk of opportunistic diseases. (Redrawn from

Fauci AS, Lane HC: Human immunodeficiency virus disease: AIDS and related conditions. In Fauci AS, et al (eds): Harrison's Principles of Internal Medicine, 14th ed. New York,

McGraw-Hill, 1997, p 1791.) B, Immune response to HIV infection. A cytolytic T lymphocyte (CTL) response to HIV is detectable by 2 to 3 weeks after the initial infection and peaks by 9

to 12 weeks. Marked expansion of virus-specific CD8+ T cell clones occurs during this time, and up to 10% of a patient's CTLs may be HIV specific at 12 weeks. The humoral immune

response to HIV peaks at about 12 weeks.

TABLE 6-13-- CDC Classification Categories of HIV Infection

CD4+ T-Cell Categories

Clinical Categories 1.³500/μL 2. 200–499/μL 3.£200/μL

A. Asymptomatic, acute (primary) HIV, or persistent generalized

lymphadenopathy

A1 A2 A3

B. Symptomatic, not A or C conditions B1 B2 B3

C. AIDS indicator conditions: including constitutional disease,

neurologic disease, or secondary infection or neoplasm

Data from CDC. Centers for Disease Control and Prevention: 1993 revised classification system and expanded surveillance definition for AIDS among adolescents and adults. MMWR 41

(RR-17): 1, 1992.

CD4+ cell count and the development of AIDS, there is extensive turnover of the virus. In other words, HIV infection lacks a phase of true microbiologic latency, that is, a phase during

which all the HIV is in the form of proviral DNA, and no cell is productively infected.

Before this discussion of the virus-host relationships is ended, some comments on those patients who are considered long-term nonprogressors are in order. Individuals in this group remain

asymptomatic for long periods of time (10 years or more), have low levels of viremia, and have stable CD4+ cell counts. People with such an uncommon clinical course have attracted

great attention in the hope that studying them may shed light on host and viral factors that influence disease progression. Studies to date suggest that this group is heterogeneous with

respect to the factors that influence the course of the disease. In a small subset of nonprogressors, the infecting HIV had deletions or mutations in the nef gene, suggesting that Nef proteins

are critical to disease progression. In most cases, the viral isolates do not show any qualitative abnormalities. In all cases, there is evidence of a vigorous anti-HIV immune response, but the

immune correlates of protection are still unknown. Some of these patients have high levels of HIV-specific CD8+ cells, and these levels are maintained over the course of infection. It is not

clear whether the robust CD8+ cell response is the cause or consequence of the slow progression. Further studies, it is hoped, will provide the answers to this and other questions critical to

disease progression.

Date: 2016-04-22; view: 767