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.

Replicative fitness of transmitted HIV-1 drives acute immune activation, proviral load in memory CD4 + T cells, and disease progression

“…Previously, our work, and that of others, showed that transmitted viral characteristics significantly correlate with early SPVL (11,13,14) as well as CD4 + T-cell decline up to 3 y postinfection (15). Here, we sought to determine the underlying mechanisms by which vRC of transmitted HIV-1 impacts the trajectory of CD4 decline even in the context of viral control by previously identified host factors, such as protective HLA alleles, that also impact disease progression.…”

“…To date, research has primarily focused on identifying host factors that contribute to viral control and favorable disease outcomes, whereas viral characteristics have received less scrutiny (10,11). HLA class I alleles such as HLA-B*57 and B*5801 have been shown to influence viral load and CD4 + T-cell decline through the induction of a strong CD8 + T-cell response that is able to target functionally vulnerable regions of the genome such as the structural protein Gag (10).…”

“…The observation that not all individuals harboring such protective HLA class I alleles go on to become long-term nonprogressors suggests that other factors outside of host immunogenetics play a role in defining disease progression (12). Transmitted viral characteristics have been shown to impact viral load within heterosexual transmission pairs, suggesting that viral characteristics are heritable and can impact disease severity (11,13,14). Moreover, we recently showed that attenuated viral replicative capacity (vRC) of the transmitted virus, defined in vitro by the Gag sequence, was associated with a significant delay in CD4 + T-cell decline in individuals recently infected with HIV-1 subtype C (15).…”

Modelling the evolution of HIV‐1 virulence in response to imperfect therapy and prophylaxis

“…Not surprisingly, then, there are conflicting reports of the strength and direction of HIV‐1 virulence evolution and the mechanisms that drive it (Blanquart et al., 2016; Fraser et al., 2014; Herbeck et al., 2012, 2016; Payne et al., 2014). Nevertheless, there is evidence that average SPVL has increased in several highly treated populations since the start of the pandemic (reviewed in Herbeck et al., 2012), and Herbeck et al.…”

“…The quantitative relationship between virulence and transmission in a human disease system has arguably been most thoroughly studied in HIV‐1 (reviewed in Fraser et al., 2014). In HIV infections, viral load refers to the density of virus in the blood stream (virions/ml of blood plasma).…”