CCR5 antagonists–with Pfizer’s maraviroc leading the development race–will be the next new antiretroviral class. These drugs bollix HIV docking to CCR5, one of two key coreceptors the virus can use to breach CD4 cells after grabbing hold of CD4 itself.

Acute HIV infection almost always involves virus that homes to the CCR5 coreceptor ("R5-tropic virus"). During advanced HIV disease the viral swarm may shift its focus to the alternate CXCR4 receptor ("X4-tropic virus") [1], but that happens in only about half of people with advanced disease.

Answers to two important questions about viral tropism will help determine how effective CCR5 antagonists will be, especially for people with virus resistant to the other classes:

• How often does HIV switch allegiance from CCR5 to CXCR4 in people with multidrug-resistant virus?
• How often will HIV jump from CCR5 to CXCR4 when pressured by CCR5 antagonists?

Partial answers to both questions emerged during the March 30-April 1 European HIV Drug Resistance Workshop in Athens.

Earlier this year Chelsea and Westminster Hospital’s Graeme Moyle published a coreceptor tropism study involving 563 people, 19% of them infected with non-subtype-B virus [2]. Only 20% of viral samples homed to CXCR4 or to both CXCR4 and CCR5, and 60% of isolates from people with a CD4 count under 100 cells/µL tracked to CCR5. But a higher CD4 count and a lower viral load did independently predict a preference for CCR5. Treatment experience, viral subtype, and mutations in reverse transcriptase or protease did not correlate with viral tropism.

A longitudinal study presented at the workshop by Rolf Kaiser (University of Cologne) confirmed the predominance of R5-tropic virus in 42 people with heavy treatment experience and multidrug-resistant HIV [3]. And Kaiser found little coreceptor switching over time.

Half of Kaiser’s cohort had AIDS, 64% had triple-class experience at the start of follow-up, and 82% had tried all three classes at the last follow-up point. All had subtype B HIV-1. The median CD4 count measured 240 cells/µL (range 10 to 1090 cells/µL) and the median viral load 27,000 copies/mL (range 276 to 1,750,000 copies/mL). Neither antiretroviral experience nor mutation patterns affected coreceptor preference. In fact the study turned up no clinical, immunologic, or virologic correlates of coreceptor tropism. But this was a small study.

Kaiser rated virus consistently R5-tropic in 25 people (59.5%) and X4-tropic in 12 (28.6%). In the other five tropism swung from X4 to R5 in two, from R5 to X4 in one, from X4 to R5 and back again in one, and from R5 to X4 to R5 in one.

HIV owes much of its infamy to a protean knack for adapting to any threat. And ever since development of CCR5 antagonists began, many have worried that virus blocked from its R5 port will simply sail on to X4. That happened rarely, however, in a maraviroc monotherapy analysis presented by Pfizer’s Elna Van Der Ryst.

Among 63 people who took Maraviroc and no other antiretrovirals, X4 viral variants cropped up in only two. Nonetheless, one of them enjoyed a 0.71-log drop in viral load and the other a 1.26-log tumble. But in a roundtable on coreceptor antagonists, Schering’s Wayne Greaves warned that emergence of X4-tropic virus remains a threat during combination therapy including a CCR5 antagonist.

What makes HIV resistant to CCR5 antagonists? The answer appears to be different for different agents, according to results presented by Pfizer’s Marilyn Lewis [4]. She ran serial passage studies with six CCR5-tropic patient isolates, exposing infected peripheral blood lymphocytes to rising doses of maraviroc for 20 passages.

Resistance-related mutations never emerged from three of the six isolates. Mutations did arise in one subtype B virus and one subtype G virus, both of which retained their CCR5 tropism. The A19T and I26V changes that emerged in the subtype B strain were distinct from those reported with another CCR5 antagonist, a prototype of Schering’s SCH-D. The changes maraviroc evoked in the subtype G virus–a triple deletion in HIV envelope’s V3 loop–differed from mutations that arose in another subtype G virus tested against SCH-C.

Maraviroc-induced mutations arose in another subtype B virus that switched tropism to CXCR4. But the same type of virus also evolved X4 tropism in a control experiment that did not subject it to maraviroc.

So far, Lewis concluded, resistance experiments with candidate CCR5 antagonists have not elicited any apparent signature mutations. And research hasn’t revealed whether CCR5-resistant virus exists naturally in viral populations not exposed to these drugs.

But one thing about this new class seems sure, noted session cochair Bonaventura Clotet: They’ll cost a lot.

Mark Mascolini writes about HIV infection (markmascolini@earthlink.net).

References
(To view slides and posters from the Third European HIV Drug Resistance Workshop, go to http://www.hivpresentation.com.)

1. Spijkerman I, de Wolf F, Langendam M, et al. Emergence of syncytium-inducing human immunodeficiency virus type 1 variants coincides with a transient increase in viral RNA level and is an independent predictor for progression to AIDS. J Infect Dis 1998;178:397-403.
2. Moyle GJ, Wildfire A, Mandalia S, et al. Epidemiology and predictive factors for chemokine receptor use in HIV-1 infection. J Infect Dis 2005;191:866-872.

3. Kaiser R, Boussaad I, Lehmann C, et al. Stable coreceptor usage of HIV-1 in patients with ongoing treatment failure on HAART. Third European HIV Drug Resistance Workshop. March 30-April 1, 2005. Athens. Abstract 60. Poster 9.5.

4. Lewis M, Westby M, Smith-Burchnell C, et al. A genotypic analysis of HIV-1 sequences from emerging resistant virus after in vitro serial passage with the CCR5 antagonist Maraviroc (UK-427857). Third European HIV Drug Resistance Workshop. March 30-April 1, 2005. Athens. Abstract 91. Poster 10.1.