Studied factor of susceptibility enhancement | Observed ↑susceptibility/infection risk | Discussion of enhancement/mechanism or potential susceptibility factor | Macaque gender/species | Virus stock/challenge dose | Study design parameters | References |
---|---|---|---|---|---|---|
Behavioral Factors of Susceptibility Enhancement | ||||||
Chronic Alcohol Use | No | Multiple, potential susceptibility factors: shifts in genital flora, increases in memory CD4+ T cells (viral targets), decreases in CD8+ T cells (anti-viral); ↑viremia in treated animals | Male and Female Rhesus | n/a | Designs vary; alcohol steadily administered via jacketed device | Loganantharaj (2014) [40]a |
Poonia (2006; AIDS)a[22] | ||||||
Poonia ([41]; JAIDS) (2006)a | ||||||
Rectal Lubricant Use | No | Acute cytotoxicity observed after application of tested lubricant, but no ↑in risk during challenge phase | Male and Female Cynomologus | SHIVSF162p3 (varying doses) | Intrarectal challenge route; AID50 dose titration model | Vishwanathan (2015) [27] |
Coinfections as Factor of Susceptibility Enhancement | ||||||
C. trachomatis/T. vaginal Coinfection (Genital Tract Infection) | Yes | 2.5-fold ↑ risk in STI-positive animals; STI-positive animals infected in fewer menstrual cycles, compared to controls (p = 0.04, log-rank; p =0.02, Fisher’s exact). Increases in mucosal pro-inflammatory cytokines during STI inoculation and SHIV challenge periods | Female Pigtail | SHIVSF162p3 (10 TCID50) | Intravaginal challenge route; repeat low-dose exposures; exposures per menstrual cycle for risk assessment | Henning (2014) [23] |
HSV-2 Coinfection (Genital Tract Infection) | Yes | Transmission not linked to active lesions. Possible HSV-2-induced immunosuppression impairs anti-SHIV response; subsequent studyb reported HSV-2 increases concentration of α4β7high CD4+ T cells (viral targets) | Female Rhesus | SHIV-RT (200 and 103 TCID50) ↑Risk with 103 | Intravaginal challenge route; animals either treated 1× or 2× with DMPA, then either 200 or 103 TCID50 | Crostarosa (2009) [22] |
Martinelli [36]b (2011) | ||||||
Malaria (Systemic Infection) | No | Evidence of potential susceptibility factors ;↑ viral load and CCR5+ CD4+ T cells (viral targets) in P. fragile-infected animals, but risk/hazard ratio not determined | Male Rhesus | SIVmac239 (103 TCID50) | Intravenous challenge route, comparing control and coinfected groups | Trott (2011) [48]a |
Schistosomiasis (Helminth/Systemic Infection) | Yes | 17-fold lower dose of virus required to infect S. mansoni-infected animals; ↑ viremia and replication in CD4+ central memory cells (viral targets) | Female Rhesus | SHIV-1157ipd3N4 (Clade C; varying doses) | Intrarectal challenge route; AID50 dose titration model | Chenine (2008) [21] |
Schistosomiasis (Helminth/Systemic Infection) | No | Intravenous challenges (compared to mucosal challenges) did not result in same increase of SHIV acquisition risk | Female Rhesus | SHIV-1157ipd3N4 (Clade C; varying doses) | Intravenous challenge route; AID50 dose titration model | Siddappa (2011) [30] |
Hormonal Factors of Susceptibility Enhancement | ||||||
Hormone Levels Associated with Menstrual Cycle Phase (Endogenous Hormone) | Yesc | Exact mechanisms to be determined. Increased rates of SHIV RNA detection in late-luteal and menses phases | Female Pigtail | SHIVSF162p3 (50 TCID50) | Intravaginal challenge route; repeat low-dose exposures | Vishwanathan (2011) [25]a |
Kersh (2014) [24]a | ||||||
Phase of Menstrual Cycle | No | Vaginal application of cell-free virus resulted in infection; 50 % of macaques infected in luteal phase, compared to 24 % challenged in follicular phase (not statistically significant) | Female Rhesus | SIVmac251 (3 × 101 to 3 × 103 TCID50, cell free; 2 to 1 × 104 infected PBMCs, cell-associated) | Compared infectivity of different doses of cell-free vs. cell-associated virus via intravaginal vs. intravenous inoculation routes | Sodora (1998) [39]d |
Progesterone Implants (Exogenous Hormone) | Yes | 7.7-fold ↑ risk in implanted animals. DMPA induced significant vaginal thinning, with ↑peak and 1st 3 months of viremia | Female Rhesus | SIVmac251 (640 TCID50) | Single intravaginal challenge with determined “minimal vaginal dose” | Marx (1996) [35] |
Vaccines as a Factor of Susceptibility Enhancement | ||||||
Ad5d Vaccine (Vaccine-induced enhancement) | Yes | ↑ risk in Ad5 seropositive animals infected with the lower (103 TCID50) challenge dose; study recapitulates lack of Ad5 vaccine efficacy and model vaccine-induced acquisition risk enhancement | Male Rhesus | SIVmac251 (varying doses) | Penile challenge route; 10-fold increases in virus concentration (103 to 105); comparisons among groups +/− Ad5 immunity, SIV vaccination, and naïve controls | Qureshi (2012) [31] |