Evidence for a Continuous Drift of the HIV-1 Species towards Higher Resistance to Neutralizing Antibodies over the Course of the Epidemic

Abstract

We compared the neutralization sensitivity of early/transmitted HIV-1 variants from patients infected by subtype B viruses at 3 periods of the epidemic (1987–1991, 1996–2000, 2006–2010). Infectious pseudotyped viruses expressing envelope glycoproteins representative of the viral quasi-species infecting each patient were tested for sensitivity to neutralization by pools of sera from HIV-1 chronically infected patients and by an updated panel of 13 human monoclonal neutralizing antibodies (HuMoNAbs). A progressive significantly enhanced resistance to neutralization was observed over calendar time, by both human sera and most of the HuMoNAbs tested (b12, VRC01, VRC03, NIH45-46G54W, PG9, PG16, PGT121, PGT128, PGT145). Despite this evolution, a combination of two HuMoNAbs (NIH45-46G54W and PGT128) still would efficiently neutralize the most contemporary transmitted variants. In addition, we observed a significant reduction of the heterologous neutralizing activity of sera from individuals infected most recently (2003–2007) compared to patients infected earlier (1987–1991), suggesting that the increasing resistance of the HIV species to neutralization over time coincided with a decreased immunogenicity. These data provide evidence for an ongoing adaptation of the HIV-1 species to the humoral immunity of the human population, which may add an additional obstacle to the design of an efficient HIV-1 vaccine.

From predicting to analyzing HIV-1 resistance to broadly neutralizing antibodies

“…The existence and significance of a trend was tested using the umbrella test and a Bonferroni correction threshold of 0.05/22 adjusting for multiple testing. When considering only the subtype B variants, the predicted IC50 values show a trend towards resistance for every bNAb confirming the results from Bouvin-Pley et al (2013). In the non-B subtype samples, a trend towards resistance was observed for Figure 4.…”

Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

“…The ability of these viruses to rapidly escape from immune pressure may suggest a role for NAbs with multiple specificities in affording protection. Indeed, many studies have shown that no single antibody specificity is likely to be effective in providing protection against diverse HIV-1 variants, but combining antibodies that target distinct neutralization epitopes increases overall neutralization coverage (282,(287)(288)(289)(290)(291)(292)(293). Currently, it is unclear whether eliciting broad and potent NAbs against multiple epitopes via vaccination is feasible, although there is evidence that such NAbs can develop within a single individual during natural HIV-1 infection (256,259,294).…”

Drift of the HIV-1 Envelope Glycoprotein gp120 toward Increased Neutralization Resistance over the Course of the Epidemic: a Comprehensive Study Using the Most Potent and Broadly Neutralizing Monoclonal Antibodies

“…Based on these hypotheses, we and others reported that HIV-1 appears to become more resistant to antibody neutralization over the course of the epidemic (33,34). In our previous study, we compared the neutralization sensitivity of early/transmitted HIV-1 variants from patients infected by subtype B viruses at three periods of the epidemic (1987 to 1991, 1996 to 2000, and 2006 to 2010).…”

“…In our previous study, we compared the neutralization sensitivity of early/transmitted HIV-1 variants from patients infected by subtype B viruses at three periods of the epidemic (1987 to 1991, 1996 to 2000, and 2006 to 2010). A progressively increasing resistance to neutralization was observed over calendar time, for both human sera and the bNAbs b12, VRC01, VRC03, NIH45-46 G54W , PG9, PG16, PGT121, PGT128, and PGT145 (33). Since then, bNAbs with increased potency or targeting different epitopes have been generated, including bNAbs improved by structure-based gene modifications (37)(38)(39)(40)(41).…”

“…The HIV-1 population that we studied was described previously (33 [CP]). For each patient, blood samples were collected shortly after infection (before 3 months postin-fection, except for a few cases).…”