MicrobiologyTier 2Medical Sciences concept

HIV cell entry mechanism (gp120, CD4, CCR5/CXCR4 coreceptors)

Core concept

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gp120 binds CD4 (the primary receptor)

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CD4 alone is not sufficient - a co-receptor is obligatory
Tropism
- R5 (CCR5-tropic, "M-tropic") - transmitted virus and acute infection; infects macrophages, dendritic cells and memory CD4 T cells
- X4 (CXCR4-tropic, "T-tropic") - emerges LATER in untreated infection in ~50%, infects naive CD4 cells -> associated with accelerated CD4 decline and progression
- Dual/mixed tropism is common

CCR5-delta32 - a 32-base-pair deletion
- Homozygotes (~1% of Northern Europeans) are highly resistant to R5 HIV infection; heterozygotes (~10-15%) progress more slowly
- Homozygotes remain susceptible to X4 virus
- The basis of the Berlin and London patient cures - allogeneic HSCT from a CCR5-delta32 homozygous donor
Entry inhibitors

Drug	Target
Maraviroc	CCR5 antagonist - requires a tropism assay first; useless against X4 or dual-tropic virus
Enfuvirtide	gp41 fusion inhibitor (subcutaneous)
Ibalizumab	Post-attachment mAb to CD4
Fostemsavir	gp120 attachment inhibitor
Lenacapavir	Capsid inhibitor (post-entry; 6-monthly subcutaneous)

Dendritic cells capture virus via DC-SIGN and carry it to lymphoid tissue - trans-infection without productive infection
CD4 depletion mechanisms: direct cytopathic killing, pyroptosis of abortively infected resting CD4 cells (the dominant mechanism), CTL killing, and chronic immune activation (microbial translocation across a damaged gut) - which is why immune activation persists and drives cardiovascular risk even on suppressive ART

Acute (primary) HIV - fever, pharyngitis, rash, lymphadenopathy, mouth ulcers, aseptic meningitis, 2-4 weeks after exposure
- Very high viraemia, high transmissibility; p24 antigen and HIV RNA are positive before antibody -> use a 4th-generation antigen/antibody assay plus HIV RNA when acute infection is suspected
- A negative antibody test does not exclude acute HIV
CD4 count predicts the opportunistic infection

CD4	Risk
<200	PJP, oesophageal candidiasis
<100	Toxoplasmosis, cryptococcus
<50	CMV retinitis, disseminated MAC

Start ART immediately at diagnosis, whatever the CD4 - INSTI-based (bictegravir/emtricitabine/TAF, or dolutegravir-based)
- Delay ART briefly in cryptococcal meningitis (IRIS risk); start within 2 weeks in TB co-infection if CD4 <50
Prevention exploits entry: PrEP (tenofovir/emtricitabine, or long-acting cabotegravir/lenacapavir), PEP within hours for 28 days, and U=U

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