Use of a small molecule CCR5 inhibitor in macaques to treat simian immunodeficiency virus infection or prevent simian-human immunodeficiency virus infection

Abstract

Human immunodeficiency virus type 1 (HIV-1) fuses with cells after sequential interactions between its envelope glycoproteins, CD4 and a coreceptor, usually CC chemokine receptor 5 (CCR5) or CXC receptor 4 (CXCR4). CMPD 167 is a CCR5-specific small molecule with potent antiviral activity in vitro. We show that CMPD 167 caused a rapid and substantial (4-200-fold) decrease in plasma viremia in six rhesus macaques chronically infected with simian immunodeficiency virus (SIV) strains SIVmac251 or SIVB670, but not in an animal infected with the X4 simian-human immunodeficiency virus (SHIV), SHIV-89.6P. In three of the SIV-infected animals, viremia reduction was sustained. In one, there was a rapid, but partial, rebound and in another, there was a rapid and complete rebound. There was a substantial delay (>21 d) between the end of therapy and the onset of full viremia rebound in two animals. We also evaluated whether vaginal administration of gel-formulated CMPD 167 could prevent vaginal transmission of the R5 virus, SHIV-162P4. Complete protection occurred in only 2 of 11 animals, but early viral replication was significantly less in the 11 CMPD 167-recipients than in 9 controls receiving carrier gel. These findings support the development of small molecule CCR5 inhibitors as antiviral therapies, and possibly as components of a topical microbicide to prevent HIV-1 sexual transmission.

Figure 1.

Structure of the CCR5 inhibitor, CMPD 167.

Figure 2.

Effect of CMPD 167 infusion into macaques infected with SIVmac251, SIVB670, or SHIV-89.6P. Twice-daily CMPD 167 therapy was commenced on day 0 (indicated by vertical line). After 14 d, therapy was administered once daily (arrowhead, 1X) for an additional 14 d, until day 28, when treatment was stopped (arrowhead, END). The dotted line indicates the viral load “baseline” at the time therapy was initiated. Each panel represents the study of an individual macaque.

Figure 3.

Absolute CD4⁺ T cell counts in the blood of three SIV-infected macaques before, during, and after treatment with CMPD 167. The pretreatment values shown were determined 164–184 d before therapy (84–104 d after infection).

Figure 4.

After the infection, viral loads in macaques were challenged vaginally with SHIV-162P4 after vaginal administration of HMC gel or CMPD 167 formulated in HMC at ∼1 mM. Two separate, but similar, experiments are shown, each performed using a different SHIV-162P4 challenge stock and a different method of quantifying viral RNA. Hence, the results are plotted separately.