Anti-V2 Antibody Deficiency in Individuals Infected With HIV-1

Abstract

25The positive correlation of high levels of plasma anti-V2 antibodies (Abs) with protective 26 immunity in the Phase III anti-HIV RV144 vaccine trial generated interest in the induction of 27 these Abs for HIV vaccine development. We analyzed plasma samples from 79 chronically 28 infected Cameroonian individuals for Ab reactivity against three V1V2 fusion proteins and five 29 cyclic V2 peptides and found that HIV-1 infection induces different levels of anti-V2 Abs. While 30 the majority of plasma samples reacted strongly with one or more V2 antigens, 10% (8) of the 31 samples were nonreactive. Deficiency of anti-V2 Abs was consistently found in longitudinal 32 plasma samples tested over 8 to 54 months of HIV infection. There was a strong correlation 33 between binding activities of plasma anti-V2 Abs and anti-gp120 and anti-gp41 Abs, suggesting 34 that deficiency of V2 Abs could be related, in part, to a limited ability to elicit strong Ab 35 responses. Analysis of gp120 sequences revealed that the V2 region of viruses from donors with 36 V2-deficient versus V2-reactive Abs displayed a tendency toward longer length, more glycans, 37 and lower isoelectric point and charge. No differences between these two patient groups were 38 noted in the same parameters measured in the V1 region. These data suggest that immunogens 39 containing a shorter V2 region with fewer glycosylation sites and higher electrostatic charges 40 would be beneficial for induction of anti-V2 Abs, but the ability to mount a strong general Ab 41 response to HIV-1 appears to be a dominant factor. 42IMPORTANCE The results of the RV144 vaccine clinical trial showed a correlation between 43 plasma Abs against a V1V2 fusion protein and a decreased risk of acquiring HIV-1 infection. 44This turned the focus of some HIV vaccine design to the induction of elevated levels of anti-V2 45Abs to increase vaccine efficacy. In plasma samples from Cameroonian individuals infected with 46 HIV-1, we observed broad variations in levels of anti-V2 Abs, and 8 of the 79 plasma samples 47 tested displayed substantial deficiency of V2 Abs. Sequence analysis of the V2 region from 48 plasma viruses and multivariate analyses of V2 characteristics showed a significant difference in 49 several features between V2-deficient and V2-reactive plasma Abs. These results suggest that 50 HIV vaccine immunogens containing a V2 region with shorter length, fewer glycosylation sites, 51 and higher electrostatic charges may be beneficial for induction of a higher level of anti-V2 Abs 52 and thus contribute to HIV vaccine efficacy. 53 54 KEYWORDS HIV-1, V1V2 region, V2 conformational antibodies, V2 linear antibodies, V2 55 antibody deficiency 56 57 4Anti-V2 antibodies (Abs) have been the subject of studies to determine their role in 58 protection against HIV-1 infection due to the results of the Phase III RV144 vaccine trial, which 59 showed an inverse correlation with risk of infection (1). The RV144 data revealed that the V2 60 Abs in vaccinees were highly cross-clade reactive and tha...