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Review
.2009 Mar;4(2):104-11.
doi: 10.1097/COH.0b013e3283224015.

CCR5 monoclonal antibodies for HIV-1 therapy

Affiliations
Review

CCR5 monoclonal antibodies for HIV-1 therapy

William C Olson et al. Curr Opin HIV AIDS.2009 Mar.

Abstract

Purpose of review: To summarize emerging clinical and preclinical data pertaining to the use of CCR5 monoclonal antibodies (mAbs) as therapies for HIV-1 infection. The epitope specificity of CCR5 mAbs is discussed in relation to its critical impact on antiviral activity and CCR5 antagonism. We compare and contrast mAbs and small-molecule CCR5 antagonists in terms of their binding and antiviral properties. Two CCR5 mAbs have entered clinical testing and have successfully completed proof-of-concept studies in HIV-infected individuals, providing initial information on the potential therapeutic utility of these agents.

Recent findings: New studies support the view that the most potent antiviral CCR5 mAbs recognize the second extracellular loop of CCR5 either exclusively or in combination with the amino terminus. Studies have revealed fundamental differences in how mAbs and small molecules bind CCR5 and inhibit HIV-1. CCR5 mAbs and small-molecule CCR5 antagonists have demonstrated consistent antiviral synergy and limited or no viral cross-resistance in independent studies. Single intravenous infusions of CCR5 mAbs significantly reduced HIV-1 RNA levels in infected individuals for 2-3 weeks without appreciable toxicity.

Summary: CCR5 mAbs have demonstrated broad and potent antiviral activity in vitro. Clinical studies have established CCR5 mAbs as potent antiretroviral agents with prolonged activity following a single dose. CCR5 mAbs represent both a distinct class of CCR5 inhibitor and a novel approach to HIV-1 therapy.

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Figures

Figure 1
Figure 1. Schematic diagram of CCR5 illustrating the binding sites for mAbs and small molecules
Amino acids are indicated in the single-letter code. Residues implicated in mAb binding are color-coded by filled symbols in the extracellular domain or sub-domain. Green = Nt; blue = ECL1; red = amino-terminal portion of ECL2; yellow = carboxy-terminal portion of ECL2. The specificities of individual mAbs are listed in Table 1. A putative binding site for maraviroc and vicriviroc in the transmembrane helices (residues W86, Y108, I198, Y251 and E283) is illustrated with magenta circles. The assignment of the seven transmembrane helices [15] is indicated with cylinders.
Figure 2
Figure 2. Antiviral activity of single-dose PRO 140 in HIV-infected adults
Subjects received single intravenous infusions of placebo (PBO) or PRO 140 at doses of 0.5 mg/kg, 2 mg/kg or 5 mg/kg. Plasma HIV-1 RNA levels were monitored for 58 days.Top panel: Percentage of subjects in each treatment group who experienced a ≥ 10-fold reduction in HIV-1 RNA at any timepoint post-treatment.Bottom panel: Mean log10 changes in HIV-1 RNA for each treatment group. Study Day 10 represents nine days post-treatment. An individual nadir represents the maximum reduction experienced by a subject at any time-point post-treatment.
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