Probes for HIV

The human immunodeficiency virus (HIV) is primarily transmitted by heterosexual contact and approximately equal numbers of men and women are infected with the virus worldwide. Understanding the biology of HIV acquisition and dissemination in men exposed to the virus by insertive penile intercourse is likely to help with the rational design of vaccines that can limit or prevent HIV transmission. To characterize the target cells and dissemination pathways involved in establishing systemic SIV infection, we necropsied male rhesus macaques at 1, 3, 7 and 14 days after penile SIV inoculation and quantified the levels unspliced SIV RNA and spliced SIV RNA in tissue lysates and the number of SIV RNA+ cells in tissues sections. We found that penile (glans, foreskin, coronal sulcus) T cells, and, to a lesser extent, macrophages and dendritic cells are primary targets of infection and that SIV rapidly reaches the regional lymph nodes. Seven days after inoculation SIV had disseminated to the blood, systemic lymph nodes and mucosal lymphoid tissues. Further, at 7 days post-inoculation (PI), spliced SIV RNA levels are highest in the genital lymph nodes indicating that this is the site where the infection is initially amplified. By 14 days PI spliced SIV RNA levels were high in all tissues, but they were highest in the gastrointestinal tract indicating that the primary site of virus replication had shifted from the genital lymph nodes to the gut. The stepwise pattern of virus replication and dissemination described here suggests that vaccine-elicited immune responses in the genital lymph nodes could help prevent the infection after penile SIV challenge.

IMPORTANCE:

To be most effective, vaccines should produce anti-viral immune responses in the anatomic sites of virus replication. Thus understanding the path taken by HIV from the mucosal surfaces, that are the site of virus exposure, to the deeper tissues where the virus replicates will provide insight into where AIDS vaccines should produce immunity to be most effective. In this study we determined that, by day 7 after penile inoculation, SIV has moved first to the inguinal lymph nodes and replicates to high levels. Although the virus is widely disseminated to other tissues by day 7, replication is largely limited to the inguinal lymph nodes. The step-by-step movement of SIV from penile mucosal surfaces to the draining lymph nodes may allow a HIV vaccine that produces immunity in these lymph nodes to block HIV from establishing an infection in an exposed person.