Rapid Dissemination of SIV Follows Multisite Entry after Rectal Inoculation

Abstract

Receptive ano-rectal intercourse is a major cause of HIV infection in men having sex with men and in heterosexuals. Current knowledge of the mechanisms of entry and dissemination during HIV rectal transmission is scarce and does not allow the development of preventive strategies. We investigated the early steps of rectal infection in rhesus macaques inoculated with the pathogenic isolate SIVmac251 and necropsied four hours to nine days later. All macaques were positive for SIV. Control macaques inoculated with heat-inactivated virus were consistently negative for SIV. SIV DNA was detected in the rectum as early as four hours post infection by nested PCR for gag in many laser-microdissected samples of lymphoid aggregates and lamina propria but never in follicle-associated epithelium. Scarce SIV antigen positive cells were observed by immunohistofluorescence in the rectum, among intraepithelial and lamina propria cells as well as in clusters in lymphoid aggregates, four hours post infection and onwards. These cells were T cells and non-T cells that were not epithelial cells, CD68+ macrophages, DC-SIGN+ cells or fascin+ dendritic cells. DC-SIGN+ cells carried infectious virus. Detection of Env singly spliced mRNA in the mucosa by nested RT-PCR indicated ongoing viral replication. Strikingly, four hours post infection colic lymph nodes were also infected in all macaques as either SIV DNA or infectious virus was recovered. Rapid SIV entry and dissemination is consistent with trans-epithelial transport. Virions appear to cross the follicle-associated epithelium, and also the digestive epithelium. Viral replication could however be more efficient in lymphoid aggregates. The initial sequence of events differs from both vaginal and oral infections, which implies that prevention strategies for rectal transmission will have to be specific. Microbicides will need to protect both digestive and follicle-associated epithelia. Vaccines will need to induce immunity in lymph nodes as well as in the rectum.

Enhanced immune activation linked to endotoxemia in HIV-1 seronegative MSM

“…Risk factors pertaining to MSM include anal intercourse [2], differences in transmission route and kinetics of viral dissemination [3], and inadequate access to preventative health care services [4-7]. Thus, MSM remain among the populations most highly affected by HIV-1 in both resource–rich and –poor settings [8].…”

Lack of Prophylactic Efficacy of Oral Maraviroc in Macaques despite High Drug Concentrations in Rectal Tissues

“…The single-layer columnar epithelium of the rectum differs from the multilayered squamous epithelium that covers the vagina and has a unique immunological composition and CCR5 distribution that may influence early establishment and dissemination of infection (14)(15)(16)(17). In humans, MVC exposure after oral dosing also differs in rectal and vaginal tissues, likely due to differences in tissue vascularization, drug trapping in mucus, and protein binding (7,8).…”

Simian Immunodeficiency Virus Infection and Mucosal Immunity

“…In GALT, virus can be detected in T cells, DC-SIGN+ cells, and other unknown subsets at this early stage (Ribeiro Dos Santos et al, 2011). However, we and others (Xu et al, 2013c) have shown that SIV infection downregulates CD3, CD4, and likely many other molecules in vivo ( Figure 3); thus, definitively determining target cell subsets in tissues remains a challenge.…”