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PA8.6 | HIV & AIDS — SDL Guide (Part 2)

Mechanisms of CD4+ T-Cell Depletion

A multi-panel medical diagram summarizes the major mechanisms causing CD4+ T-cell depletion in HIV infection, including cytopathic injury, immune killing, pyroptosis, syncytium formation, thymic failure, and chronic immune activation. — **Panel A:** Overview of multifactorial CD4+ T-cell depletion with HIV virions, declining CD4+ count, normal range 500-1500 cells/uL, and AIDS threshold <200 cells/uL.. **Panel B:** Direct viral cytopathic effect showing viral budding, plasma membrane disruption, and toxic unintegrated viral DNA.. **Panel C:** Immune-mediated killing showing CD8+ CTL destruction of infected CD4+ T cells and NK-cell ADCC against antibody-coated infected cells.. **Panel D:** Pyroptosis showing abortive infection of bystander CD4+ T cells, incomplete viral DNA, inflammasome activation, caspase-1, and IL-1beta/IL-18 release.. **Panel E:** Syncytium formation showing gp120 binding to CD4 receptors on neighboring cells and formation of a multinucleated giant cell.. **Panel F:** Thymic damage showing HIV infection of thymic progenitors with reduced naive CD4+ T-cell replenishment.. **Panel G:** Chronic immune activation showing gut barrier disruption, microbial translocation, persistent immune activation, immune exhaustion, and activation-induced apoptosis..

CD4+ T-cell destruction is multifactorial — no single mechanism is sufficient:

Direct viral cytopathic effect — viral budding disrupts plasma membrane; accumulation of unintegrated viral DNA is toxic
Immune-mediated killing — CD8+ cytotoxic T cells (CTLs) kill HIV-infected CD4+ cells; ADCC (antibody-dependent cellular cytotoxicity) by NK cells
Pyroptosis (major mechanism for abortive infection): CD4+ bystander T cells ingest incomplete viral DNA → inflammasome activation (caspase-1) → inflammatory programmed death → releases IL-1β and IL-18 (fuelling immune activation)
Syncytium formation — gp120 on infected cells binds CD4 on uninfected neighbours → multinucleate giant cells, killed by fusion
Thymic damage and failure — HIV infects thymic progenitors, reducing naïve CD4+ replenishment
Chronic immune activation — persistent microbial translocation (gut mucosal barrier disruption) drives immune exhaustion and activation-induced apoptosis

Normal CD4+ count: 500–1500 cells/µL. AIDS is defined by CD4 < 200 cells/µL.

Natural History of HIV Infection — Three Phases

HIV infection follows a predictable natural course over years to decades if untreated.

Phase 1 — Acute HIV Infection (Acute Seroconversion Illness):
• 2–4 weeks post-infection; presents as a flu/infectious-mononucleosis-like illness: fever, sore throat, lymphadenopathy, myalgia, maculopapular rash
• Viraemia peaks at 10⁶–10⁷ copies/mL; CD4 count drops sharply (may fall below 200 transiently)
• Host immune response (CTLs + antibodies) partially controls virus; CD4 count recovers but not to baseline
• Window period: ELISA becomes positive 3–12 weeks post-infection; p24 antigen positive 2–4 weeks (earlier); RNA PCR positive within days — explains the hook scenario

Phase 2 — Chronic HIV Infection / Clinical Latency:
• Lasts 8–10 years (untreated average); virus is NOT truly latent — active replication continues (~10⁹ virions produced daily)
• Gradual CD4 decline (~50–80 cells/µL per year); patient may be asymptomatic or have persistent generalised lymphadenopathy (PGL)
• Viral load settles at a set point (individual viral load plateau) — predictor of progression speed
• Late in latency: constitutional symptoms (weight loss, night sweats, oral candida, herpes zoster) as CD4 approaches 200

Phase 3 — AIDS (Acquired Immune Deficiency Syndrome):
• CD4 < 200 cells/µL OR presence of an AIDS-defining illness (regardless of CD4 count)
• Without treatment, progression to AIDS: median 10 years; death within 1–2 years of AIDS diagnosis

A timeline graph of untreated HIV infection showing acute viraemia, chronic latency with gradual CD4 decline, and progression to AIDS below the CD4 200 threshold. — **Panel A:** Natural history graph with time axis, CD4+ T-cell count curve, HIV RNA viral load curve, viral set point, CD4 < 200 AIDS threshold, and three phase bands.. **Panel B:** Acute seroconversion illness with fever, sore throat, lymphadenopathy, myalgia, maculopapular rash, RNA PCR window, p24 antigen window, and ELISA antibody window.. **Panel C:** Chronic HIV infection / clinical latency with active lymph node replication, CD4+ T cells, HIV virions, viral load set point, persistent generalized lymphadenopathy, gradual CD4 decline, and late-latency symptoms.. **Panel D:** AIDS phase with CD4 < 200 cells/uL, AIDS-defining illness, opportunistic infection, wasting, median untreated progression, and untreated survival after AIDS diagnosis..

CLINICAL PEARL

The set point viral load after acute infection is the single best predictor of the rate of CD4 decline and time to AIDS — more predictive than the CD4 count at that time. A patient with a set point of 30,000 copies/mL will progress ~3× faster than one with a set point of 1,000. This is why clinicians check both CD4 count and viral load at every HIV visit: CD4 tells you where the patient is now; viral load tells you how fast they're travelling.

SELF-CHECK

A 34-year-old woman is diagnosed with HIV. Her CD4 count is 420 cells/µL and viral load is 85,000 copies/mL. She feels well. Which statement best characterises her current stage?

A. AIDS — she should be started on prophylaxis for Pneumocystis jirovecii pneumonia immediately

B. Chronic HIV infection / clinical latency — active viral replication ongoing despite apparent wellness

C. Acute seroconversion illness — the high viral load indicates she was infected within the last 4 weeks

D. Undetectable HIV — the CD4 count is normal so she does not require ART yet

Reveal Answer

Answer: B. Chronic HIV infection / clinical latency — active viral replication ongoing despite apparent wellness

A CD4 count > 200 with symptoms absent places her in chronic (clinical latency) phase. However, 'latency' is a misnomer — ~10⁹ new virions are produced daily. Her high viral load (85,000 copies/mL) indicates fast progression; current guidelines recommend ART for all HIV+ individuals regardless of CD4 count, urgently so with high viral load. PCP prophylaxis is not yet indicated (CD4 > 200). Acute seroconversion presents much earlier (weeks).

Opportunistic Infections Stratified by CD4+ Count

As CD4+ T-cell count falls, the immune deficiencies manifest in a characteristic sequence. Knowing the CD4 threshold for each infection is essential for clinical diagnosis and prophylaxis decisions.

CD4 range	Pathogens / infections
< 500	Tuberculosis (all forms, may reactivate at any CD4), oral candidiasis, recurrent bacterial pneumonia, herpes zoster
< 200	Pneumocystis jirovecii pneumonia (PCP) (formerly P. carinii) — bilateral interstitial infiltrates, dry cough, hypoxia; classic AIDS-defining infection
< 100	Toxoplasma gondii encephalitis (ring-enhancing brain lesions, seizures); Cryptococcus neoformans meningitis (India ink stain, cryptococcal antigen)
< 50	Cytomegalovirus (CMV) retinitis (flame haemorrhages + cotton-wool spots → blindness); Mycobacterium avium complex (MAC) (fever, night sweats, hepatosplenomegaly, anaemia)

Also important:
• Candida oesophagitis (CD4 < 100–200): odynophagia, barium swallow shows shaggy oesophagus
• Cryptosporidium diarrhoea: severe, watery, chronic (CD4 < 100)
• Progressive multifocal leukoencephalopathy (PML): JC virus reactivation → demyelination (CD4 < 100)

A horizontal CD4 decline timeline links immune suppression thresholds to characteristic opportunistic infections in HIV/AIDS. — **Panel A:** Declining CD4+ T-cell count timeline with thresholds at 500, 200, 100, and 50 cells/microliter. **Panel B:** CD4 <500: tuberculosis, oral candidiasis, recurrent bacterial pneumonia, herpes zoster. **Panel C:** CD4 <200: Pneumocystis jirovecii pneumonia with bilateral interstitial infiltrates, dry cough, hypoxia, AIDS-defining infection. **Panel D:** CD4 <100: Toxoplasma gondii encephalitis with ring-enhancing brain lesions and Cryptococcus neoformans meningitis with India ink and cryptococcal antigen. **Panel E:** CD4 <50: CMV retinitis with flame hemorrhages and cotton-wool spots, and Mycobacterium avium complex with systemic symptoms. **Footer:** Candida oesophagitis at CD4 <100-200 with odynophagia and shaggy oesophagus, and Cryptosporidium diarrhea.