Phylodynamics of HIV-1 from a Phase-III AIDS Vaccine Trial in North America

Abstract

In 2003, a phase III placebo-controlled trial (VAX004) of a candidate HIV-1 vaccine (AIDSVAX B/B) was completed in 5,403 volunteers at high risk for HIV-1 infection from North America and the Netherlands. A total of 368 individuals became infected with HIV-1 during the trial. The envelope glycoprotein gene (gp120) from the HIV-1 subtype B viruses infecting 349 patients was sequenced from clinical samples taken as close as possible to the time of diagnosis, rendering a final data set of 1,047 sequences (1,032 from North America and 15 from the Netherlands). Here, we used these data in combination with other sequences available in public databases to assess HIV-1 variation as a function of vaccination treatment, geographic region, race, risk behavior, and viral load. Viral samples did not show any phylogenetic structure for any of these factors, but individuals with different viral loads showed significant differences (P = 0.009) in genetic diversity. The estimated time of emergence of HIV-1 subtype B was 1966–1970. Despite the fact that the number of AIDS cases has decreased in North America since the early 90s, HIV-1 genetic diversity seems to have remained almost constant over time. This study represents one of the largest molecular epidemiologic surveys of viruses responsible for new HIV-1 infections in North America and could help the selection of epidemiologically representative vaccine antigens to include in the next generation of candidate HIV-1 vaccines.

Genetic and epidemiological insights into the emergence of peste des petits ruminants virus (PPRV) across Asia and Africa

“…Interestingly, the estimates of the viral genetic diversity are between 10 and 100, which are consistent with the estimates reported for other paramyxoviruses31. However, the estimates are significantly lower than those previously reported in chronic infections such as HIV404142 and hepatitis C4344. Such low levels of PPRV-IV diversity indicate that frequent population bottlenecks are likely to purge out the diseased individuals from the populations, and therefore, limiting the genetic variation31.…”

Sequences in Glycoprotein gp41, the CD4 Binding Site, and the V2 Domain Regulate Sensitivity and Resistance of HIV-1 to Broadly Neutralizing Antibodies

“…The specimens used for swarm analysis were selected on the basis of being from recent infections (mean time after infection, 109 Ϯ 58 days), without regard for whether they were from vaccine or placebo groups. Because there was no evidence of vaccine efficacy in this trial and because no differences were detected between vaccinees and placebo recipients with respect to virus loads, CD4 counts, time to initiation of antiretroviral therapy (14,17), or phylogenetic differences in Env sequences (45), samples from both groups were selected at random for use in these studies.…”

“…Libraries of full-length Env genes were isolated from cryopreserved plasmas from 57 subjects who became infected with HIV-1 while participating in a phase 3 trial (14) of a candidate HIV-1 vaccine (AIDSVAX B/B) (1). The specimens selected for analysis were provided by Global Solutions for Infectious Diseases (GSID) (South San Francisco, CA) and represented the earliest postinfection sam-ples available, with an estimated mean time after infection of 109 Ϯ 58 days (45). Libraries representing the Env variants from the swarm of quasispecies that evolved in each infection were constructed at Monogram Biosciences (South San Francisco, CA) by PCR amplification and then cloned into the expression vector pCXAS-PXMX as described previously (42,43,66).…”

Magnitude and Breadth of a Nonprotective Neutralizing Antibody Response in an Efficacy Trial of a Candidate HIV‐1 gp120 Vaccine

“…Beyond Vax004, for efficacy trials with evidence for positive vaccine efficacy, a larger effect of this kind could indicate that some circulating viruses are more sensitive to vaccine-elicited NAbs that blocked their transmission to exposed vaccine recipients. We encourage similar assessments of NAbs, combined with complementary genetic analyses of the viruses (49), in RV144 and future trials where measurable protection is achieved.…”