Paper # 511|
Reduced Viral Replication and Limited env Diversification in Macaques Failing Oral ARV PrEP
Q Zheng, W Switzer, W Heneine, and Gerardo Garcia-Lerma*
CDC, Atlanta, GA, US
Background: Pre-exposure prophylaxis (PrEP) with
antiretroviral (ARV) drugs is a promising HIV prevention strategy and its
efficacy is being evaluated in humans. Acute infection in persons who fail PrEP
will inevitably occur under concurrent therapy, thus raising questions
regarding the potential impact of PrEP on early viral dynamics and evolution.
We investigated acute viremias and virus evolution rates in a macaque PrEP
model of rectal simian/human immunodeficiency virus (SHIV) infection.
Methods: Peak viremias were measured in 35 rhesus
macaques infected rectally with SHIV162p3. Of these animals, 6 were infected
during daily PrEP with emtricitabine (FTC) or tenofovir/emtricitabine (TNV/FTC),
7 were infected during intermittent PrEP with TNV/FTC, and 22 were untreated
controls. env sequence evolution was monitored by single genome
amplification in 2 untreated controls and 4 PrEP failures that continued
treatment for 13 to 28 weeks after infection. For each animal, a total of 20 to
30 env sequences (V1-V5) were obtained both at peak viremia and during
18 to 29 weeks. None of the specimens had reverse transcriptase drug resistance
Results: Peak viremias in daily (median = 4.9 log10
RNA copies/mL; min, max = 3.5, 7.1) or intermittent PrEP failures (median = 5.6;
min, max = 3.2, 6.6) were significantly lower than in untreated controls
(median = 7.2 log10; min, max = 5.3, 8.9) (p = 0.007 and p
= 0.008, respectively). Analysis of env sequences from 4 PrEP failures
and 2 untreated controls showed evidence of infection by a single variant in
all cases. Mean nucleotide divergence from SHIV162p3 was significantly lower in
PrEP failures than in control animals both at peak viremia (0.04 and 0.1
substitutions per site, respectively, p <0.005) and after 18 to 29
weeks (0.27 and 0.77 substitutions per site, respectively, p <0.005).
Maximum env diversity in PrEP failures was 0.26% compared to 1.07% in untreated
control animals. Overall virus diversity was lower in PrEP failures both at
peak viremia (0.025% vs 0.049% in controls, p <0.005) and after 18 to
29 weeks (0.13% vs 0.83% in controls, p <0.005).
Conclusions: We show in macaques that PrEP with FTC
or TNV/FTC significantly limits env sequence evolution during early
infection, likely reflecting the antiviral activity of drugs in reducing virus
replication. Decreased acute viremia and limited virus evolution may reduce
early CD4 depletion and potentially enhance immune control by slowing the
selection of escape mutants.