Progestin-based contraceptive suppresses cellular immune responses in SHIV-infected rhesus macaques

Abstract

Nine rhesus macaques in groups of three received a single dose of the injectable progestin-based contraceptive Depo-Provera 5 weeks prior to challenge intravaginally with varying doses of a mixture of the pathogenic CXCR4 (X4)-SHIV(SF33A) and CCR5 (R5)-SHIV(SF162P3) isolates. As controls, seven Depo-naive animals were inoculated once with a high-dose of the mixed inoculum. Irrespective of inoculum dose, acute viremia was higher in the Depo-treated than in the Depo-naive animals. Further, genetic complexity of the replicating virus was greater and replication of the X4 virus was favored in dually infected animals treated with Depo-Provera. Analysis of cellular immune responses revealed slower response rates in virus-specific IFN-gamma production to SIV Gag in the Depo-treated macaques. The immunosuppressive effect of Depo-Provera on mounting an antiviral cellular immune response may account for the increase viral burden and diversity, and the predominance of X4 virus replication in SHIV infected macaques that were administered the progestin-based contraceptive.

RT-SHIV, an infectious CCR5-tropic chimeric virus suitable for evaluating HIV reverse transcriptase inhibitors in macaque models

“…Similarly, the antibody response was highly variable and overall lower in most of the DMPA macaques compare to the non-DMPA group. Immunosuppression has been noted previously in DMPA-treated macaques [38]. These investigators have also indicated low virus-specific IFN-gamma production in DMPA-treated macaques in response to SIV Gag.…”

“…These investigators have also indicated low virus-specific IFN-gamma production in DMPA-treated macaques in response to SIV Gag. The immunosuppressive effect of DMPA on antiviral immune response may at least in part account for the increased viral burden and the diversity in antibody level seen in this study and by others [38]. Nevertheless, our findings with non-DMPA treated macaques indicate that this RT-SHIV virus is highly infectious and readily transmissible through vaginal mucosa in pigtail macaques.…”

“…DMPA causes non-physiological thinning of vaginal epithelia to enhance virus penetration through mucosa. Also, evidence suggests that DMPA may have global effects on immune system as mentioned earlier [38]. On the other hand, repeated low-dose model may achieve a high rate of macaque infection through large number of mucosal exposures; however, it is proved to be highly labor intensive, expensive and technically challenging.…”

“…However, recently, mucosal transmission of RT-SHIV have been reported by two laboratories [34,35] in which all rhesus macaques had been pretreated with DMPA (Depo Provera ® ) before intravaginal viral exposure. It is known that prior administration of DMPA enhances mucosal viral transmission by thinning of the vaginal epithelium [37] and also possibly by suppression of antiviral immune response [38]. …”

Accelerated immune senescence and reduced response to vaccination in ovariectomized female rhesus macaques

“…Despite intense research, we do not yet fully understand the contribution of other age-related physiological changes to immune senescence. Several studies have shown that female sex hormones modulate immune response during infection and autoimmune diseases (Ansar Ahmed and Talal 1989;Gillgrass et al 2003;Gillgrass et al 2005;Kaushic et al 1998;Marx et al 1996;Smith et al 2000;Trunova et al 2006). However, the impact of ovarian steroids loss associated with menopause on immune senescence and the immune response to infection or vaccination remains unknown.…”