Induction of potent local cellular immunity with low dose X4 SHIVSF33A vaginal exposure

Abstract

Intravaginal inoculation of rhesus macaques with varying doses of the CXCR4 (X4)-tropic SHIV(SF33A) isolate revealed a threshold inoculum for establishment of systemic virus infection and a dose dependency in overall viral burden and CD4+ T cell depletion. While exposure to inoculum size of 1000 or greater 50% tissue infectious dose (TCID(50)) resulted in high viremia and precipitous CD4+ T cell loss, occult infection was observed in seven of eight macaques exposed to 500 TCID(50) of the same virus. The latter was characterized by intermittent detection of low level virus with no evidence of seroconversion or CD4+ T cell decline, but with signs of an ongoing antiviral T cell immune response. Upon vaginal re-challenge with the same limiting dose 11-12 weeks after the first, classic pathogenic X4 SHIV(SF33A) infection was established in four of the seven previously exposed seronegative macaques, implying enhanced susceptibility to systemic infection with prior exposure. Pre-existing peripheral SIV gag-specific CD4+ T cells were more readily demonstrable in macaques that became systemically infected following re-exposure than those that were not. In contrast, early presence of circulating polyfunctional cytokine secreting CD8+ T cells or strong virus-specific proliferative responses in draining lymph nodes and in the gut associated lymphoid tissue (GALT) following the first exposure was associated with protection from systemic re-infection. These studies identify the gut and lymphoid tissues proximal to the genital tract as sites of robust CD8 T lymphocyte responses that contribute to containment of virus spread following vaginal transmission.

Repeated Exposure to Trace Amounts of Woodchuck Hepadnavirus Induces Molecularly Evident Infection and Virus-Specific T Cell Response in the Absence of Serological Infection Markers and Hepatitis

“…As indicated, this discordance between anti-WHV T cell and antibody responses was associated with the lack of protection against infection with a liver-pathogenic dose of the same virus, suggesting that the antibodies played an essential role in preventing symptomatic infection. This concurs with the observations made in asymptomatic infections caused by other viruses, such as hepatitis C virus (HCV) (64)(65)(66), human immunodeficiency virus (HIV) (67), or simian immunodeficiency virus (SIV) (68), wherein virus-specific T cell proliferative and cytotoxic T lymphocyte (CTL) reactivity occur in the absence of serological or pathological evidence of infection with the respective virus.…”

A feline immunodeficiency virus vif-deletion mutant remains attenuated upon infection of newborn kittens

“…Persistence of virus-specific cellular immune responses exhibited by cats after FIV-pPPRDvif DNA inoculation was interesting, considering the absence of any detectable viraemia. Similar observations of strong SIV-specific T-cell proliferative responses despite weak antiviral antibody responses were also described for occult SIV and simianhuman immunodeficiency virus infections in rhesus macaques induced by vaginal delivery of low dose virus inoculum (McChesney et al, 1998;Tasca et al, 2007). Future examination of mechanisms for these persistent cellular responses may be warranted to identify potential FIV-pPPRDvif-permissive cell populations or reservoirs in the host and provide additional insights into Vif interactions with cellular proteins in vivo.…”

Small Ruminant Lentiviruses and Human Immunodeficiency Virus: Cousins that Take a Long View

“…The results suggest that the infection was either transient or became occult. Transient or occult infection also occurs in SIV, FIV and other retroviruses [179][180][181][182] and so appears to be a general feature of lentivirus infections.…”