Globally, human immunodeficiency virus-type 1 (HIV-1) is extraordinarily variable, and this diversity poses a major obstacle to AIDS vaccine development. Currently, candidate vaccines are derived from isolates, with the hope that they will be sufficiently cross-reactive to protect against circulating viruses. This may be overly optimistic, however, given that HIV-1 envelope proteins can differ in more than 30% of their amino acids. To contend with the diversity, country-specific vaccines are being considered, but evolutionary relationships may be more useful than regional considerations. Consensus or ancestor sequences could be used in vaccine design to minimize the genetic differences between vaccine strains and contemporary isolates, effectively reducing the extent of diversity by half.

More detailed sequence standards that keep up with revolutionary sequencing technologies will aid the research community in evaluating data.

Designing an effective human immunodeficiency virus type 1 (HIV-1) vaccine will rely on understanding which variants, from among the myriad of circulating HIV-1 strains, are most commonly transmitted and determining whether such variants have an Achilles heel. Here we show that heterosexually acquired subtype A HIV-1 envelopes have signature sequences that include shorter V1-V2 loop sequences and fewer predicted N-linked glycosylation sites relative to the overall population of circulating variants. In contrast, recently transmitted subtype B variants did not, and this was true for cases where the major risk factor was homosexual contact, as well as for cases where it was heterosexual contact. This suggests that selection during HIV-1 transmission may vary depending on the infecting subtype. There was evidence from 23 subtype A-infected women for whom there was longitudinal data that those who were infected with viruses with fewer potential N-linked glycosylation sites in V1-V2 had lower viral set point levels. Thus, our study also suggests that the extent of glycosylation in the infecting virus could impact disease progression.Studies in the simian immunodeficiency virus (SIV)/macaque model of AIDS have shown that the viruses that evolve over the course of disease are selected in part because they increase the number and/or vary the position of the carbohydrates to shield them from the host antibody response (1, 15). Subsequent studies indicate that a similar evolutionary process may occur in the human immunodeficiency virus type 1 (HIV-1) envelope during both simian/human immunodeficiency virus infection in macaques (2) and HIV-1 infection in humans (17). A recent study of eight individuals infected with subtype C HIV-1 suggested that there may be counterselection at transmission against variants with long hypervariable loops and relatively large numbers of potential N-linked glycosylation sites, which are predicted to have a more recessed receptor-binding domain (4). The transmitted subtype C HIV-1s had signature sequence characteristics, which included shorter envelope variable loop domains and fewer potential N-linked glycosylation sites (PNGS) (4). Because the study was limited to a small number of cases, all of one subtype, it is unclear whether transmission of viruses with these characteristics is typical, a point that is of importance for designing globally effective vaccines and other interventions to block transmitted viruses.We examined HIV-1 sequences within a median of 70 days (interquartile range [IQR], 49 to 161) post negative serology (PNS) from 27 women and eight men from Kenya who acquired subtype A HIV-1 through heterosexual transmission (8, 9, 13; unpublished data). The days PNS was defined as the time from the last HIV-1-negative serological test to when the sample used to obtain sequences was taken. The sequences were compared to subtype A sequences in the Los Alamos database to determine if they differed in V1-V2 length or number of PNGS. The Los Alamos database includes sequences from su...

Current knowledge of human immunodeficiency virus type 1 envelope (Env) glycoprotein structure and function is based on studies of clade B viruses. We present evidence of sequence and structural differences in viral glycoprotein gp120 between clades B and C. In clade C, the C3 region ␣2-helix exhibits high sequence entropy at the polar face but maintains its amphipathicity, whereas in clade B it accommodates hydrophobic residues. The V4 hypervariable domain in clade C is shorter than that in clade B. Generally, shorter V4 loops are incompatible with a glycine occurring in the ␣2-helix in clade C, an intriguing association that could be exploited to inform Env immunogen design.The genetic diversity of human immunodeficiency virus type 1 (HIV-1) is characterized by a relatively small number of genetically defined clades, or subtypes, A to K, and their recombinants (11). The envelope (Env) glycoproteins gp120 and gp41 are the main targets of antibody neutralization and are among the most variable of HIV proteins, with typical interclade and intraclade differences of 20 to 35% and 10 to 15%, respectively (7). An antibody-based HIV vaccine would ideally be capable of neutralizing viruses from diverse variants. Whether this will be feasible and how one might design a polyvalent cocktail that could improve the cross-reactive breadth of vaccine-induced responses can be informed by detailed examination of clade-specific differences in structure and mutational patterns.Different regions of Env are under profoundly different selective pressures in the different clades (2, 7). Such differences could result from the evolution of lineage-specific structural or functional constraints in the proteins. They could also be due to transmission pressures (1a, 4, 6), spatially localized differences in neutralizing antibody binding sites (15), or different HLA frequencies in the circulating populations (12) and the consequent immune escape pressures. Codon-specific ratios of nonsynonymous to synonymous substitution rates (dN/dS; where a high ratio is indicative of positive as well as diversifying selection) (17) are dramatically different in the B-and C-clade V3 and C3 regions of gp120 (2, 7). The V3 loop from clade B has a high density of states with dN/dS of Ͼ1, whereas those from clade C show little variation (8). Conversely, clade C is more variable in the C3 region, particularly in the ␣2-helix, which is relatively conserved in clade B (2, 7). Neutralization studies on C-clade transmission pair Envs found ␣2-helix resistance-associated mutations (14a), indicating that immune pressure could be directed against it. Here we explore mutational patterns and their structural implications to better understand how positive selection might be driven by immune escape.The analysis of clade differences is based on 582 C-clade and 634 B-clade sequences from the LANL HIV database as of January 2005. Subsets of 120 early and 68 late C sequences and 241 early and 211 late B sequences are also analyzed, where "early" and "late" sequences are defi...

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