Virulence and pathogenesis of HIV-1 infection: an evolutionary perspective

Abstract

Why some individuals develop AIDS rapidly whereas others remain healthy without treatment for many years remains a central question of HIV research. An evolutionary perspective reveals an apparent conflict between two levels of selection on the virus. On the one hand, there is rapid evolution of the virus in the host, and on the other, new observations indicate the existence of virus factors that affect the virulence of infection whose influence persists over years in infected individuals and across transmission events. Here, we review recent evidence that shows that viral genetic factors play a larger role in modulating disease severity than anticipated. We propose conceptual models that reconcile adaptive evolution at both levels of selection. Evolutionary analysis provides new insight into HIV pathogenesis.

Box Figure 1

Phylogeny of HIV isolated from 134 Swiss men who have sex with men (left) with well-defined SPVL (indicated by the color of tips). Heritability is estimated by comparing phylogenetic proximity to similarity in SPVL (16).

Figure 1. the evolutionary epidemiology of viral load.

A, the typical pattern of viral load in untreated HIV-1 infection, with a very high peak during the first weeks of infection, and a gradual increase in the late stages of infection. During asymptomatic infection, viral loads are often relatively steady, fluctuating around a value known as the set-point viral load (SPVL). B, the distribution of SPVL in a cohort of patients infected with subtype B virus; the distribution is similar across populations and across viral subtypes (69). Note the log-scale on the x-axis, which demonstrates variability over orders of magnitude. To illustrate the extraordinary extent of this variability, inset plots show simulated viral density in 5μL of peripheral blood for two values at either side of the distribution of viral load: thus viral load is a strong predictor of both infectiousness and rate of progression to disease The distribution of SPVL was previously described with (7), and we have updated this to include SPVL data from 2,015 seroconverters in the cohort (with kind permission from Drs. de Wolf and Reiss). (C). Infectiousness, estimated within heterosexual couples, is shown in blue. The severity of infection, estimated as the mean time from seroconversion to AIDS, is shown in green (from (7)). Lines show best fit, and filled areas show 95% confidence intervals. D, the transmission potential is a summary measure of the epidemiological ‘success’ of an infection with given set-point viral load: it is the mean number of expected secondary infections over the whole chronic and asymptomatic infectious life-span, estimated as the product of infectiousness and duration of asymptomatic infection (from C). The close agreement in between the optimal evolutionary strategy (labeled in D) and the distribution of viral loads (plotted in B) suggested the hypothesis that the distribution of viral loads is in fact the outcome of viral adaptation to maximize the transmission potential (7). None of the calculations account for the effect of treatment. This is reasonable for of an evolutionary analysis, since treatment has unfortunately only become widely available in recent years.

Figure 2. mechanisms that could reconcile rapid within-host evolution with heritability of SPVL and adaptation to maximize transmission opportunities.

A, Illustration of a full transmission-to-transmission viral replication cycle. During or shortly after transmission, the virus experiences a very strong bottleneck (70), and expands clonally, mostly in activated CD4+ T-cells. Most viral replication is very fast, with a cellular life-cycle of one or two days (39, 40), but a reservoir of virus in long-lived CD4 cells is quickly established, is continuously replenished, and persists for life (52). Viral replication quickly becomes systemic, assisted by chronic and persistent immune activation, with gut-associated lymphatic tissue and germinal centres in other lymphatic tissues being particularly privileged sites of replication (52, 58). The most uncertainty in the lifecycle surrounds which viruses, if any, are preferentially transmitted to found new infections in other hosts. (B-D) Three mechanisms that could reconcile within-host adaptation with heritability and population-level viral evolution to maximize transmission; these mechanisms are described by schematic representations of the viral lifecycle. In mechanism 1 (B), population-level evolution is explained by evolutionary constraints that slow within-host evolution of virulence traits in the host, perhaps due to virulence genotypes requiring complex combinations of mutations rather than individual non-interacting point mutations. In mechanism 2 (C), population-level evolution is explained by an absence of selection within the host for viral virulence factors. In mechanism 3 (D), population-level evolution is explained by separation of within-host and between-host adaptation caused by preferential transmission of viruses that are stored during early infection, together with disproportionate influence of the founder genotype on SPVL.