What is the role of a CCR8 (chemokine receptor 8) antagonist in the treatment of HIV (human immunodeficiency virus)?

CCR8 Antagonists Have No Established Role in HIV Treatment

CCR8 antagonists are not part of standard HIV treatment and are not recommended in any current clinical guidelines. The established HIV entry inhibitors target CCR5 (such as maraviroc) and CXCR4, not CCR8 1, 2.

Current Standard HIV Entry Inhibitors

CCR5 Antagonists (Approved and Used)

• Maraviroc is the only FDA-approved coreceptor antagonist for HIV treatment, specifically targeting CCR5 1, 3
• Maraviroc is approved for treatment-experienced patients with exclusively R5 (CCR5-tropic) virus strains 1
• CCR5 antagonists like maraviroc and the investigational vicriviroc are allosteric, noncompetitive antagonists that bind to CCR5 and prevent HIV entry 1, 3
• These agents demonstrated efficacy and tolerability in HIV-infected patients in Phase III trials 3

CXCR4 Antagonists (Investigational Only)

• CXCR4 antagonists including T22, T140, TC14012, AMD3100, ALX40-4C, and KRH-1120 have been synthesized but remain investigational 4
• These agents inhibit X4-HIV-1 infection through specific binding to CXCR4 4
• No CXCR4 antagonist has achieved FDA approval or guideline recommendation for clinical use 1, 2

CCR8 as a Coreceptor: Research Findings Only

Limited Clinical Relevance

• CCR8 can serve as an alternative coreceptor for some HIV-1 and HIV-2 isolates in laboratory studies 5
• CCR8 usage was observed more frequently in HIV-1 than HIV-2 isolates in research settings 5
• Despite laboratory evidence of CCR8 usage, no CCR8 antagonists have been developed for clinical use 5

Why CCR8 Is Not a Therapeutic Target

• CCR5 and CXCR4 remain the primary coreceptors of clinical importance 1, 3, 6
• CCR5-tropic strains are the most frequently sexually transmitted and clinically relevant 3, 6
• The natural CCR5-delta32 deletion confers resistance to HIV infection without obvious phenotype, making CCR5 a validated therapeutic target 3, 6
• No similar natural deletion or clinical validation exists for CCR8 as a therapeutic target 5

Current Guideline-Recommended HIV Treatment

First-Line Therapy

• Integrase strand transfer inhibitor (InSTI)-based regimens are the optimal initial therapy, specifically bictegravir or dolutegravir plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) 1, 2
• These regimens have high barriers to resistance, low pill burden, and do not require pharmacologic boosting 2

Entry Inhibitor Use (When Applicable)

• Coreceptor tropism testing is required before using CCR5 antagonists to confirm the virus uses only CCR5 1
• Maraviroc is reserved for treatment-experienced patients with documented CCR5-tropic virus 1, 3
• Entry inhibitors are not first-line therapy and represent a specialized treatment option 1, 2

Clinical Pitfalls to Avoid

• Do not confuse research on alternative coreceptors (like CCR8) with clinically available therapies 5
• Do not use CCR5 antagonists without documented CCR5-tropic virus, as approximately 50% of patients develop CXCR4-tropic virus over time 3
• Recognize that the ability of some viral isolates to use alternative coreceptors like CCR8 could theoretically impact entry inhibitor efficacy, but this remains a research concern without clinical therapeutic implications 5
• Focus on guideline-recommended InSTI-based regimens for initial therapy rather than entry inhibitors 1, 2