Abstract:Mother-to-child transmission (MTCT) of HIV-1 provides a model for studying the role of passively acquired antibodies in preventing HIV infection. We determined the titers of neutralizing antibodies (NAbs) against six primary isolates of clades B and CRF01_AE in sera from 45 transmitting and 45 nontransmitting mothers matched for the main independent factors associated with MTCT in Thailand. A lower risk of MTCT, particularly for intrapartum transmission, was associated only with higher NAb titers against the C… Show more
“…To investigate to what extent the V1V2 domain might contribute to the particular resistance of clone 11005CL7 to 2G12, we constructed two chimeric env genes in which the V1V2 domains of 11005CL7 and 5008CL2 were swapped using a domain exchange strategy, as previously described (28,30). The chimeric 5008CL2env⌬V1V2[V1V2 11005CL7 ] (CHIM1) expressed the V1V2 domain of 11005CL7 in the 5008CL2 env backbone, whereas the chimeric 11005CL7env⌬V1V2 [V1V2 5008CL2 ] (CHIM2) expressed the V1V2 domain of 5008CL2 in the 11005CL7 recipient env (Fig.…”
The broadly neutralizing human monoclonal antibody 2G12 binds to a carbohydrate-dependent epitope involving three major potential N-linked glycosylation sites (PNGS) of gp120 (N295, N332, and N392). Through analysis of the sensitivity to 2G12 of pseudotyped viruses carrying envelope proteins from HIV-1 clade B-infected long-term nonprogressors, we selected two naturally occurring env clones with opposite sensitivities to 2G12, albeit harboring the 3 particular PNGS known to be essential for 2G12 binding (N295, N332, and N392). The resistant clone presented a long and potentially heavily glycosylated V1V2 loop and an additional PNGS (N302) in the V3 loop. The sensitive clone harbored a short V1V2 loop and lacked the PNGS at N302. We created chimeric envelope genes by swapping the V1V2 domains of the two env clones. The influence of N302 on 2G12 sensitivity was assessed by PCR-based site-directed mutagenesis. Both the exchange of the V1V2 domain and the introduction of the PNGS at N302 on the 2G12-sensitive clone induced a significant decrease in sensitivity to 2G12. In contrast, the reverse V1V2 exchange and the removal of the PNGS at N302 on the 2G12-resistant clone increased sensitivity to 2G12, confirming the influence of these regions on 2G12 sensitivity. Our results, supported by a molecular-modeling study, suggest that both the V1V2 loop and an additional PNGS in V3 might limit access to the 2G12 epitope.
“…To investigate to what extent the V1V2 domain might contribute to the particular resistance of clone 11005CL7 to 2G12, we constructed two chimeric env genes in which the V1V2 domains of 11005CL7 and 5008CL2 were swapped using a domain exchange strategy, as previously described (28,30). The chimeric 5008CL2env⌬V1V2[V1V2 11005CL7 ] (CHIM1) expressed the V1V2 domain of 11005CL7 in the 5008CL2 env backbone, whereas the chimeric 11005CL7env⌬V1V2 [V1V2 5008CL2 ] (CHIM2) expressed the V1V2 domain of 5008CL2 in the 11005CL7 recipient env (Fig.…”
The broadly neutralizing human monoclonal antibody 2G12 binds to a carbohydrate-dependent epitope involving three major potential N-linked glycosylation sites (PNGS) of gp120 (N295, N332, and N392). Through analysis of the sensitivity to 2G12 of pseudotyped viruses carrying envelope proteins from HIV-1 clade B-infected long-term nonprogressors, we selected two naturally occurring env clones with opposite sensitivities to 2G12, albeit harboring the 3 particular PNGS known to be essential for 2G12 binding (N295, N332, and N392). The resistant clone presented a long and potentially heavily glycosylated V1V2 loop and an additional PNGS (N302) in the V3 loop. The sensitive clone harbored a short V1V2 loop and lacked the PNGS at N302. We created chimeric envelope genes by swapping the V1V2 domains of the two env clones. The influence of N302 on 2G12 sensitivity was assessed by PCR-based site-directed mutagenesis. Both the exchange of the V1V2 domain and the introduction of the PNGS at N302 on the 2G12-sensitive clone induced a significant decrease in sensitivity to 2G12. In contrast, the reverse V1V2 exchange and the removal of the PNGS at N302 on the 2G12-resistant clone increased sensitivity to 2G12, confirming the influence of these regions on 2G12 sensitivity. Our results, supported by a molecular-modeling study, suggest that both the V1V2 loop and an additional PNGS in V3 might limit access to the 2G12 epitope.
“…2A). Recent studies on CRF01_AE (40,47) and subtype C Env (39) showed that viral susceptibility to neutralizing antibodies was inversely correlated with the length of V1 and V2 regions of Env gp120. In addition, several CRF01_AE Env clones that contain a long V2 region, similar to 65CC1 (46), were resistant to b12-mediated neutralization (47).…”
A recombinant human monoclonal antibody, IgG1 b12 (b12), recognizes a conformational epitope on human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) gp120 that overlaps the CD4 binding domain. Although b12 is able to broadly neutralize HIV-1 subtype B, C, and D viruses, many HIV-1 CRF01_AE viruses are resistant to b12-mediated neutralization. In this report, we examined the molecular mechanisms underlying the low neutralization susceptibility of CRF01_AE viruses to b12, using recently established CRF01_AE Env recombinant viruses. Our results showed that two potential N-linked glycosylation (PNLG) sites in the V2 and C2 regions of Env gp120 played an important role in regulating the susceptibility of CRF01_AE Env to b12. The locations of these PNLG sites correspond to amino acid positions 186 and 197 in HXB2 Env gp120; thus, they are designated N186 and N197 in this study. Removal of N186 significantly conferred the b12 susceptibility of 2 resistant CRF01_AE Env clones, 65CC4 and 107CC2, while the introduction of N186 reduced the b12 susceptibility of a susceptible CRF01_AE Env clone, 65CC1. In addition, removal of both N186 and N197 conferred the b12 susceptibility of 3 resistant CRF01_AE Env clones, 45PB1, 62PL1, and 101PL1, whereas the removal of either N186 or N197 was not sufficient to confer the b12 susceptibility of these CRF01_AE Env clones. Finally, removal of N197 conferred the b12 susceptibility of 2 resistant CRF01_AE Env clones lacking N186, 55PL1 and 102CC2. Taken together, we propose that two PNLG sites, N186 and N197, in Env gp120 are important determinants of the b12 resistance of CRF01_AE viruses.
“…In a Thai study of maternal antibodies and MTCT, there was evidence that the neutralizing potential against one particular regional HIV-1 strain was correlated with infant infection (2,43). It is difficult to compare these studies directly because the prior study examined antibodies in the maternal index case, while ours focused on antibodies in the exposed infant.…”
Section: Discussionmentioning
confidence: 97%
“…Several early studies, each relatively small, showed that nontransmitting mothers had more frequently detected and/or higher levels of NAb responses than transmitting mothers, suggesting a role for NAb in reducing MTCT (7,16,22,45,46). A correlation between maternal antibodies and transmission risk was also observed in a larger study of Thai women (n ϭ 90), in which the potency of NAb responses to 2 of 4 viruses tested inversely correlated with transmission (2,43). Subsequent studies showed that the variants transmitted to infants tended to be those in the mother that were the most resistant to NAbs (10,51).…”
Although a major goal of human immunodeficiency virus type 1 (HIV-1) vaccine efforts is to elicit broad and potent neutralizing antibodies (NAbs), there are no data that directly demonstrate a role for such NAbs in protection from HIV-1 infection in exposed humans. The setting of mother-to-child transmission provides an opportunity to examine whether NAbs provide protection from HIV-1 infection because infants acquire passive antibodies from their mothers prior to exposure to HIV-1 through breastfeeding. We evaluated the characteristics of HIV-1-specific NAbs in 100 breast-fed infants of HIV-1-positive mothers who were HIV-1 negative at birth and monitored them until age 2. A panel of eight viruses that included variants representative of those in the study region as well as more diverse strains was used to determine the breadth of the infant NAbs. From their mothers, infants acquired broad and potent NAbs that were capable of recognizing heterologous circulating HIV-1 variants of diverse subtypes, but the presence of NAbs of broad HIV-1 specificity was not associated with transmission risk. There was also no correlation between responses to any particular virus tested, which included a range of diverse variants that demonstrated different neutralization profiles, including recognition by specific antibodies with known epitope targets. The eight viruses tested exhibited neutralization profiles to a variety of monoclonal antibodies (2F5, PG9, and VRC01) similar to those of viruses present in pregnant women in the cohort. These results suggest that the breadth and potency of the heterologous antibody response in exposed infants, measured against a virus panel comprised of variants typical of those circulating in the population, does not predict protection.
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