Neutralizing antibody responses drive the evolution of human immunodeficiency virus type 1 envelope during recent HIV infection

Abstract

HIV type 1 (HIV-1) can rapidly escape from neutralizing antibody responses. The genetic basis of this escape in vivo is poorly understood. We compared the pattern of evolution of the HIV-1 env gene between individuals with recent HIV infection whose virus exhibited either a low or a high rate of escape from neutralizing antibody responses. We demonstrate that the rate of viral escape at a phenotypic level is highly variable among individuals, and is strongly correlated with the rate of amino acid substitutions. We show that dramatic escape from neutralizing antibodies can occur in the relative absence of changes in glycosylation or insertions and deletions (''indels'') in the envelope; conversely, changes in glycosylation and indels occur even in the absence of neutralizing antibody responses. Comparison of our data with the predictions of a mathematical model support a mechanism in which escape from neutralizing antibodies occurs via many amino acid substitutions, with low cross-neutralization between closely related viral strains. Our results suggest that autologous neutralizing antibody responses may play a pivotal role in the diversification of HIV-1 envelope during the early stages of infection.selection ͉ glycosylation

Synonymous Substitution Rates Predict HIV Disease Progression as a Result of Underlying Replication Dynamics

“…To demonstrate this, we further analyzed env sequences sampled through time from two patients with markedly distinct rates of phenotypic escape from nAb responses [31] (patient 01-0083 and patient 01-0127; Figure 4). As in Frost et al [2], we show that the virus that rapidly escaped nAb responses in patient 01-0127 accumulated nonsynonymous substitutions at a considerably higher rate on backbone branches, while synonymous divergence rates appear to be unaffected (similar plots were obtained for internal branches, unpublished data).…”

“…Our results show that the nonsynonymous rates in the env gene, most likely effecting phenotypic escape from nAbs ( Figure 4, [2]), do not correlate with disease progression in patients harbouring HIV-1 group M viruses. While these conclusions are based on serial sampled data for only two patients, Frost et al [2] have clearly demonstrated this effect in multiple patients. Crucially, we show that the selection pressure on env obscures the expected correlation between overall nucleotide substitution rates and disease progression, emphasizing the need to disentangle the contributions of synonymous and nonsynonymous substitutions to HIV evolution.…”

“…Both the Shankarappa et al [14] C2V3 env sequence data and the [27] follow-up sequences were analyzed. Complete env gene sequences longitudinally sampled from two patients with distinct phenotypic escape form nAbs were obtained from Frost et al [2]. Heterochronous HIV-1 group O env data were obtained from the two available intrapatient evolution studies [33,36].…”

“…Both humoral and cell-mediated immune responses are mounted against the virus but are eventually defeated by HIV replication and adaptation. As part of this process, neutralizing antibodies (nAbs) exert a strong selective pressure on the HIV envelope gene (env) [1,2] but do not control viral replication, and nAb levels are not predictive of disease progression [3]. Cytotoxic T cell (CTL) responses play a more important protective role in HIV infection, and evidence has shown that partial control of HIV replication in vivo is temporally associated with the appearance of CTL responses [4] and that the rate of disease progression is strongly dependent on human leukocyte antigen (HLA) class I alleles [5,6].…”

Surveillance programs for detection and characterization of emergent pathogens and antimicrobial resistance: results from the Division of Infectious Diseases, UNIFESP

“…Mechanisms of humoral escape include: hiding of critical neutralizing epitopes, extension of gp120 variable loops, conformational protection of viral receptor binding motifs, and extensive glycosylation of envelope surface proteins. It has been demonstrated that acutely infected patients produce NAbs against autologous virus within months of seroconversion (Albert et al 1990, Tremblay and Wainberg 1990, Richman et al 2003, Wei et al 2003, Frost et al 2005), but although the early produced NAbs reach fairly high titers, escape mutants are rapidly selected due to the ongoing viral replication (Richman et al 2003, Wei et al 2003. It also has been shown that chronically HIV-1 infected patients develop NAbs against earlier viral isolates, but they fail to neutralize contemporaneous virus (Albert et al 1990, Tremblay and Wainberg 1990, Skrabal et al 2005).…”