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.
Highlights
Despite widely available prevention modalities against HIV transmission, 2.6 million individuals are newly infected with HIV every year
HIV-1 infects fully activated memory CD4+ T cells. These events represent a critical point in transmission because they lead to high-level replication and the migration of virus into draining lymphoid tissue and gut-associated lymphoid tissue (GALT) where activated CD4+ T cells are plentiful, viral replication amplifies and the high level viremia that is associated with acute infection is established[9]
The best opportunity to prevent or abort establishment of HIV infection is likely during the eclipse phase following transmission, before HIV-1 migrates into the GALT
Summary
Despite widely available prevention modalities against HIV transmission, 2.6 million individuals are newly infected with HIV every year. One can infer that, following deposition on the mucosal surface of the genital tract, HIV very frequently fails to establish infection Both human and an SIV/macaque model studies indicate that during the first days of infection, termed the ‘‘eclipse phase’’, low levels of viral replication occur, primarily in suboptimally activated memory CD4+ T cells in the genital mucosa[3,4,5,6,7,8]. These cells are metabolically active, they do not express classical activation markers[4,7]. The best opportunity to prevent or abort establishment of HIV infection is likely during the eclipse phase following transmission, before HIV-1 migrates into the GALT
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