The Genotype of Early-Transmitting HIV gp120s Promotes α4β7 –Reactivity, Revealing α4β7+/CD4+ T cells As Key Targets in Mucosal Transmission

Abstract

Mucosal transmission of HIV is inefficient. The virus must breach physical barriers before it infects mucosal CD4+ T cells. Low-level viral replication occurs initially in mucosal CD4+ T cells, but within days high-level replication occurs in Peyer's patches, the gut lamina propria and mesenteric lymph nodes. Understanding the early events in HIV transmission may provide valuable information relevant to the development of an HIV vaccine. The viral quasispecies in a donor contracts through a genetic bottleneck in the recipient, such that, in low-risk settings, infection is frequently established by a single founder virus. Early-transmitting viruses in subtypes A and C mucosal transmission tend to encode gp120s with reduced numbers of N-linked glycosylation sites at specific positions throughout the V1-V4 domains, relative to typical chronically replicating isolates in the donor quasispecies. The transmission advantage gained by the absence of these N-linked glycosylation sites is unknown. Using primary α4β7 +/CD4+ T cells and a flow-cytometry based steady-state binding assay we show that the removal of transmission-associated N-linked glycosylation sites results in large increases in the specific reactivity of gp120 for integrin- α4β7. High-affinity for integrin α4β7, although not found in many gp120s, was observed in early-transmitting gp120s that we analyzed. Increased α4β7 affinity is mediated by sequences encoded in gp120 V1/V2. α4β7-reactivity was also influenced by N-linked glycosylation sites located in C3/V4. These results suggest that the genetic bottleneck that occurs after transmission may frequently involve a relative requirement for the productive infection of α4β7 +/CD4+ T cells. Early-transmitting gp120s were further distinguished by their dependence on avidity-effects to interact with CD4, suggesting that these gp120s bear unusual structural features not present in many well-characterized gp120s derived from chronically replicating viruses. Understanding the structural features that characterize early-transmitting gp120s may aid in the design of an effective gp120-based subunit vaccine.

Role of donor genital tract HIV-1 diversity in the transmission bottleneck

“…We and others have reported that founder viruses generally have fewer glycosylation sites and more compact Envs (9,(31)(32)(33), and our earlier studies also demonstrated that newly transmitted viruses were not escape variants from PL-neutralizing antibodies in the donor (9). Recent studies have suggested that subtype A and C founder viruses bind efficiently to the gut homing receptor α4β7 expressed on a subset of highly susceptible CD4 T lymphocytes and that this property can be reduced with evolution of the virus after transmission (34). Collectively, the current study and these previous studies point to selection for a virus variant with a set of essential biological properties during transmission.…”

The Thai Phase III HIV Type 1 Vaccine Trial (RV144) Regimen Induces Antibodies That Target Conserved Regions Within the V2 Loop of gp120

“…23,24,36,[65][66][67] Rolland et al have reported that sieve mutations in HIV-1 breakthrough infections in RV144 contain mutations at positions 169 and 181 in V2. 50 T cell epitope mapping studies using PBMCs from HIV-1-uninfected RV144 vaccine recipients and the interferon-gamma ELISpot assay also showed preferential targeting of the V2 loop and that the responding cells were CD4…”

HIV-1 Pathogenesis: The Virus

“…Similarly, infected T cells could migrate to different body compartments to deliver virus. Finally, it has been suggested that the viral Env protein in the transmitted virus acts as a mimic of a4b7 integrin to target virus to CD4 þ T cells in the GALT (Nawaz et al 2011); a corollary of this model is that viruses without this feature might initiate a local mucosal infection but not establish a systemic infection because of failure to traffic to the GALT. If stable infections were failing because of an absence of the ability to mimic a4b7 integrin to target GALT one might expect to see seroconversion based on transient replication in the proximal mucosal tissues, as is seen for HSV-2 infection, but this is not observed for putative abortive HIV-1 infections.…”