Evidence for potent autologous neutralizing antibody titers and compact envelopes in early infection with subtype C human immunodeficiency virus type 1

Abstract

Information about neutralizing antibody responses in subtype C-infected individuals is limited, even though this viral subtype causes the majority of AIDS cases worldwide. Here we compared the course and magnitude of the autologous neutralizing antibody (NAb) response against viral envelope (Env) glycoproteins present during acute and early infection with subtypes B and C human immunodeficiency virus type 1 (HIV-1). NAb responses were evaluated in 6 subtype B-infected and 11 subtype C-infected subjects over a mean evaluation period of 25 months using a pseudovirus reporter gene assay. All subjects in the C cohort were infected through heterosexual contact, while five of the six subjects in the B cohort were infected via male-to-male contact. The kinetics and magnitude of the NAb responses varied among subjects in the B and C cohorts; however, the median 50% inhibitory concentration (IC(50) titer) reached by antibody in the plasma of subtype C-infected subjects, overall, was 3.5-fold higher than in the subtype B-infected subjects (P = 0.06). The higher titers of NAbs in the C cohort were associated with viruses having significantly shorter amino acid length (P = 0.002) in the V1 to V4 region of the surface Env glycoprotein, gp120, compared to the B cohort. Despite the potency of the autologous subtype C NAb response, it was not directed against cross-neutralizing epitopes. These data demonstrate that subtype C Envs elicit a potent yet restricted NAb response early in infection that frequently reaches IC(50) titers in excess of 1:1,000 and suggest that clade-specific differences may exist in Env immunogenicity or susceptibility to neutralization.

FIG. 1.

Course and magnitude of autologous neutralizing antibody responses against Envs in subtype C- and B-infected subjects. The IC₅₀ plasma dilution against virus pseudotyped with autologous Envs derived during acute/early infection is plotted vertically on a log 10 scale. The collection time (in months) of each plasma sample tested is shown on the horizontal axes. Envs were cloned at the first time point only. The Env pseudotypes tested for each subject are indicated in each panel, and NAb responses against each Env are represented by colored lines with symbols. M or F indicates a male or female subject, respectively; PB or PL indicates that the Env was cloned from PBMC DNA or plasma, respectively. (A) Autologous NAb responses in 11 subtype C-infected seroconvertors are shown against individual Env pseudotypes. The initial samples were collected when the subjects were first seropositive, within 4 months (129 days) of the last seronegative test (time zero). Subjects 201 M and 242 F were viral p24 antigen positive at the first time point analyzed; subjects 185 F and 205 F were viral p24 antigen positive at time zero. (B) Autologous NAb responses in six subtype B-infected acutely infected subjects against individual Env pseudotypes. The initial samples were collected within 31 days of the onset of symptoms (time zero).

FIG. 2.

Comparison of subtype B and subtype C subjects. Vertical point plots were generated to display the peak IC₅₀ titer (A), the month of the peak titer (B), the set point (last available) plasma viral load (C), the length of the gp120 V1-V4 region (D), and the number of N-linked glycosylation sites in the V1-V4 region (E). Each point represents a subtype B- or subtype C-infected subject. For peak IC₅₀ titer, month of peak titer, V1-V4 length, and number of N-gly sites, a median value was used for each subject. The bar represents the group median. Group medians were compared using a nonparametric Mann-Whitney test and are reported when the P value was less than or approaching 0.05. Subtype B subjects, n = 6; subtype C subjects, n = 11. Plasma viral load data were not available for subject 153 M.

FIG. 3.

Correlation between V1-V4 length, glycosylation, and neutralization susceptibility. Correlation plots were generated for peak IC₅₀ titer versus V1-V4 length (A), V1-V4 length versus number of N-gly sites (B), and peak IC₅₀ titer versus number of N-gly sites (C) using median values for the 17 subjects. Each point represents an individual subject. Correlations were evaluated using the nonparametric Spearman Rank test and the correlation coefficient (ρ) is reported when the P value was less than 0.05.