Deep Gene Sequence Cluster Analyses of Multi-Virus-Infected Mucosal Tissue Reveal Enhanced Transmission of Acute HIV-1

Abstract

Exposure of the genital mucosa to a genetically diverse viral swarm from the donor HIV-1 can result in breakthrough and systemic infection by a single transmitted/founder (TF) virus in the recipient. The highly diverse HIV-1 envelope (Env) in this inoculating viral swarm may have critical role in transmission and subsequent immune response. Thus, chronic (Envchronic) and acute (Envacute) Env chimeric HIV-1 were tested using multi-virus competition assays in human mucosal penile and cervical tissues. Viral competition analysis revealed that Envchronic viruses resided and replicated mainly in the tissue while Envacute viruses penetrated the human tissue and established infection of CD4+ T cells more efficiently. Analysis of the replication fitness, as tested in peripheral blood mononuclear cells (PBMCs), showed similar replication fitness of Envacute and Envchronic viruses, which did not correlate with transmission fitness in penile tissue. Further, we observed that chimeric env viruses with higher replication in genital mucosal tissue (chronic Env viruses) had higher binding affinity to C-type lectins. Data presented herein suggests that the inoculating HIV-1 may be sequestered in the genital mucosal tissue (represented by chronic Env HIV-1) but that a single HIV-1 clone (e.g. acute Env HIV-1) can escape this trapped replication for systemic infection. Importance During heterosexual HIV-1 transmission, a genetic bottleneck occurs in the newly infected individual as the virus passes from the mucosa and leading to systemic infection of a single transmitted HIV-1 clone in the recipient. This bottleneck in the recipient has just been described and the mechanisms involved in this selection process have not been elucidated. However, understanding mucosal restriction is of the utmost importance to understanding dynamics of infections and to now design focused vaccines. Using our human penile and cervical mucosal tissue models for mixed HIV infections, we provide evidence that HIV-1 from acute/early as compared to chronic infection can more efficiently traverse the mucosal epithelium and transmitted to T cells, suggesting higher transmission fitness. These studies focused on the role of the HIV-1 envelope in transmission and provides strong evidence that HIV transmission may involve breaking the mucosal lectin trap.

HIV-1 Entry and Prospects for Protecting against Infection

“…Although HIV-infected individuals harbor a pool of HIV quasispecies, infection is typically initiated by only one variant, termed the T/F virus, following mucosal transmission. The selection of the T/F virus is a multifactorial process resulting from positive and negative selection pressure in the mucosa [ 18 , 29 ]. Below we discuss the phenotypic and antigenic characteristics of T/F viruses and how these attributes might be exploited to block infection onset [ 30 ].…”