HIV pathogenesis: dynamics and genetics of viral populations and infected cells

Abstract

In the absence of treatment, HIV-1 infection, usually starting with a single virion, leads inexorably to a catastrophic decline in the numbers of CD4(+) T cells and to AIDS, characterized by numerous opportunistic infections as well as other symptoms, including dementia and wasting. In the 30 years since the AIDS pandemic came to our attention, we have learned a remarkable amount about HIV-1, the responsible virus--the molecular details about how it functions and interacts with the host cell, its evolution within the host, and the countermeasures it has evolved to overcome host defenses against viral infection. Despite these advances, we remain remarkably ignorant about how HIV-1 infection leads to disease and the death of the human host. In this brief article, we introduce and discuss important lessons that we have learned by examining the dynamics of viral populations and infected cells. These studies have revealed important features of the virus-host interaction that now form the basis of our understanding of the importance and consequence of ongoing viral replication during HIV-1 infection.

Figure 1.

Time course of typical HIV infection. Patterns of CD4⁺ T cell decline and viremia vary greatly from one patient to another. (From Fauci and Desrosiers 1997; reprinted, with permission, from Cold Spring Harbor Laboratory Press © 1997.)

Figure 2.

Relationship between viral load (viremia) and clinical progression. Shown are Kaplan–Meier plots of AIDS-free survival divided into quartiles according to virus load (A) or CD4 count (B) at the time of diagnosis. (From Fauci and Desrosiers 1997; reprinted, with permission, from Cold Spring Harbor Laboratory Press © 1997.)

Figure 3.

Decay of circulating virus and infected cells after initiation of suppressive antiviral therapy. These results imply the presence of at least four classes of HIV-infected cells: productively infected, a second class, perhaps macrophages, with a half-life of ∼2 wk; latently infected resting CD4 cells, with a half-life of ∼6 mo; and long-lived DNA positive cells, most of which are nonproductive. A fourth class of infected cells, inferred to have an approximately infinite half-life, is not shown. (Figure modified from Fauci and Desrosiers 1997.)

Figure 4.

Typical evolution of HIV after infection. (A) The level of viremia (orange) and the genetic diversity, measured as the average pairwise difference (black) of the HIV population as a function of time after infection. (B) Phylogenetic relationship of HIV-1 sequences at various stages of infection. The colored circles correspond to sequences of plasma virus RNA sampled at the corresponding time points in A: At peak viremia (yellow), the viral population (in most patients) is highly uniform, diversifying gradually over the first few years of infection. Samples taken from chronic infection (green and blue) are considerably more diverse, but take 3 yr or more to diverge perceptibly (red). Following initiation of suppressive therapy, divergence ceases, even after long times (orange, gray). After years of therapy, clonal populations of virus arise in some patients (black).