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Table 1 Literature Review of Macaque Models of Enhanced HIV Risk

From: Macaque models of enhanced susceptibility to HIV

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]

  1. Relevant literature is grouped by type of susceptibility enhancement factor, with description of study design, parameters, and analytical approach and effect(s) of enhancement factor(s)
  2. Terminology of ‘increased infections in experimental animals over controls’ and ‘increased (↑) risk/susceptibility’ is synonymous with observed enhancement of SIV/SHIV infection susceptibility due to or attributed to the studied (potential) enhancement factor
  3. aCitations describe studies not reporting or not designed to demonstrate enhanced susceptibility, but describe potential or key susceptibility factors for HIV/SIV/SHIV infection
  4. bFollow-up study to Crostarosa, et al. [22] publication, investigating mechanisms of HSV-2-induced enhanced susceptibility
  5. cAssessed retrospectively, during specific phases of the menstrual cycle
  6. dAd5 – Adenovirus, serotype 5