Occult Systemic Infection and Persistent Simian Immunodeficiency Virus (SIV)-Specific CD4⁺-T-Cell Proliferative Responses in Rhesus Macaques That Were Transiently Viremic after Intravaginal Inoculation of SIV

Abstract

The intact cervicovaginal mucosa is a relative barrier to the sexual transmission of human immunodeficiency virus type 1 (HIV-1). In the simian immunodeficiency virus (SIV) macaque model of HIV infection, seronegative transient viremia (STV; virus isolation positive followed by repeated negative cultures) occurs after intravaginal inoculation of a low dose of pathogenicSIVmac251 (C. J. Miller, M. Marthas, J. Torten, N. Alexander, J. Moore, G. Doncel, and A. Hendrickx, J. Virol. 68:6391-6400, 1994). Thirty-one adult female macaques that had been inoculated intravaginally with pathogenic SIVmac251 became transiently viremic. One monkey that had been culture negative for a year after SIV inoculation became persistently viremic and developed simian AIDS. No other STV monkey developed persistent viremia or disease. Results of very sensitive assays showed that 6 of 31 monkeys had weak SIV-specific antibody responses. SIV-specific antibodies were not detected in the cervicovaginal secretions of 10 STV monkeys examined. Twenty of 26 monkeys had lymphocyte proliferative responses to p55 gag and/or gp130 env antigens; 3 of 6 animals, including the monkey that became persistently viremic, had detectable cytotoxic T-lymphocyte (CTL) responses to SIV. At necropsy, lymphoid tissues and vaginal mucosa were virus culture negative, but in 10 of 10 animals, SIV provirus was detected by PCR using gag-specific primer pairs. Fifty percent of the PCR-positive tissue samples were also positive for SIV gag RNA by reverse transcriptase PCR. Thus, transient viremia following intravaginal inoculation of pathogenic SIV is associated with persistent, systemic infection, either latent or very low level productive. Atypical immune responses, characterized by lymphocyte proliferation and some CTL responses in the absence of conventionally detectable antibodies, develop in transiently viremic monkeys.

Immunology of pediatric HIV infection

“…Interestingly, transient infection or occult systemic low-level infection has been documented in both adult and infant macaque models of SIV and SHIV (308,(314)(315)(316). Notably, in a few cases of low-level infection, rebound viremia occurred following a year or more of aviremic survival (314)(315)(316). The implications of these findings in reference to the recent 'functional cure' of an infant (317) still need to be determined (see section on the possibility of cure below).…”

Factors Associated with Slow Disease Progression in Macaques Immunized with an Adenovirus-Simian Immunodeficiency Virus (SIV) Envelope Priming-gp120 Boosting Regimen and Challenged Vaginally with SIVmac251

“…Occult infection of macaques following vaginal infection with SIV has recently been reported (47), raising the possibility that the slow disease progression of macaque 353 was simply a manifestation of this phenomenon rather than a consequence of vaccination-induced immune responses. This does not seem to be the case, since in animals with natural occult infections, detection of virus or viral nucleic acids is very rare.…”

Cellular Superspreaders: An Epidemiological Perspective on HIV Infection inside the Body

“…Second, such short-lived ''local outbreaks'' of HIV within an individual could still yield a low level of virus production, even if the initial outbreak of HIV infection ultimately goes extinct. Among a group of nonhuman primates exposed to a low physiological dose of SIV, some animals experienced initial low levels of viral replication and immune response without ever proceeding to full infection or seroconversion, a phenomenon called occult infection [62][63][64]. In addition, some HIV-exposed, seronegative humans who continue to engage in high-risk sexual behavior exhibit immunological markers that indicate a prior immune response to HIV infection even though they remain seronegative, supporting the idea that local infections may have occurred in these patients [65][66][67].…”