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HIV: Overview and Pathophysiology

What is HIV?

HIV (Human Immunodeficiency Virus) is an RNA retrovirus belonging to the genus Lentivirus. There are two types: HIV-1 (the dominant global form) and HIV-2 (mostly confined to West Africa). Left untreated, HIV progressively destroys cellular immunity, eventually resulting in AIDS (Acquired Immunodeficiency Syndrome).

As of 2022, approximately 39 million people worldwide were living with HIV, with ~67% in Sub-Saharan Africa. Antiretroviral therapy (ART) has transformed HIV from a fatal illness into a manageable chronic condition, with life expectancy now approaching that of the general population in treated individuals.

Harrison's Principles of Internal Medicine 22e (2025)

The Virus

HIV is a retrovirus. Its key structural and functional features:

Component	Role
gp120 (surface glycoprotein)	Binds CD4 receptor on host T cells
gp41 (transmembrane glycoprotein)	Mediates membrane fusion
Reverse transcriptase	Converts viral RNA to DNA (essential drug target)
Integrase	Integrates viral DNA into host genome
Protease	Cleaves polyprotein precursors into mature virions
CCR5 / CXCR4 (host co-receptors)	Required alongside CD4 for viral entry

The HIV Life Cycle (6 Steps)

Attachment - gp120 binds CD4 on T cells/macrophages; co-receptor (CCR5 or CXCR4) binding follows
Fusion - gp41 drives the viral envelope to fuse with the host cell membrane
Reverse transcription - Viral RNA is converted to double-stranded DNA by reverse transcriptase (the most exploited drug target)
Integration - Viral DNA is inserted into the host genome by integrase (forming the "provirus")
Transcription & Translation - Host cell machinery transcribes viral genes into mRNA and viral proteins
Assembly, budding & maturation - New virions assemble and bud from the cell; protease cleaves polyproteins into functional units

Each step is a drug target, forming the basis of modern ART classes (NRTIs, NNRTIs, INSTIs, PIs, entry inhibitors).

Kaplan & Sadock's Comprehensive Textbook of Psychiatry

Primary Target Cells

HIV infects cells expressing CD4:

CD4+ T helper cells (main target - progressive depletion drives immunodeficiency)
Macrophages (serve as a long-lived viral reservoir)
Dendritic cells (aid in viral dissemination to lymph nodes)

Phases of Disease and Pathogenesis

1. Acute Phase (Primary Infection, weeks 1-4)

After mucosal exposure, the virus undergoes an initial "eclipse phase" - undetectable in plasma for days
Virus replicates in mucosal CD4+ T cells, draining lymph nodes, then disseminates widely
GALT (gut-associated lymphoid tissue) is massively seeded - memory CD4+ T cells there are infected and depleted by direct viral killing and activation-induced apoptosis
A burst of high-level plasma viremia occurs
Acute HIV syndrome appears: flu-like illness (fever, lymphadenopathy, rash, myalgia)
Viral RNA peaks, then CD8+ T cell responses partially suppress viremia

2. Latent (Chronic) Phase (months to years)

Low-level viral replication continues in lymphoid tissues
CD4+ count slowly declines from normal (~500-1500 cells/µL) toward ~350 cells/µL
Patient may be asymptomatic
Persistent immune activation and chronic inflammation continue to drive cell death
HIV establishes latent reservoirs in resting memory T cells and macrophages - these cannot be cleared by current ART

3. Advanced Disease / AIDS

CD4+ count falls below 200 cells/µL (AIDS-defining threshold in the USA)
Susceptibility to opportunistic infections (OIs): Pneumocystis jirovecii pneumonia, CMV, Toxoplasma, Mycobacterium avium complex, cryptococcal meningitis
AIDS-defining malignancies: Kaposi sarcoma, primary CNS lymphoma, invasive cervical cancer
HIV encephalopathy and wasting syndrome
Harrison's Principles of Internal Medicine 22e (2025), Cellular and Molecular Immunology (9e)

Mechanisms of CD4+ T Cell Depletion

Several mechanisms operate simultaneously:

Direct cytolysis - viral replication leads to cell lysis during budding
Immune clearance - CD8+ cytotoxic T cells kill HIV-infected cells
Pyroptosis - caspase-1-mediated inflammatory cell death in tissue CD4+ T cells undergoing abortive (non-productive) HIV infection
Activation-induced apoptosis - chronic immune activation drives T cell exhaustion and death
Immune exhaustion - persistent antigen stimulation causes functional T cell dysfunction even before numerical depletion

The result is a quantitative and qualitative failure of CD4+ T cell immunity.

Harrison's Principles of Internal Medicine 22e (2025)

Viral Reservoirs - The Cure Problem

HIV establishes long-lived reservoirs that persist despite ART:

Reservoir	Lifespan
Activated CD4+ T cells	Short-lived
Macrophages	Longer-lived
Follicular helper T cells	Long-lived
Resting memory CD4+ T cells (especially mucosal)	Very long-lived - main barrier to cure

Because the proviral DNA in resting memory cells is transcriptionally silent, the immune system cannot recognize and eliminate these cells. ART suppresses viral replication but does not clear these reservoirs. This is why stopping ART leads to viral rebound within weeks.

Why HIV Evades Immunity

Extremely high mutation rate - reverse transcriptase lacks proofreading, generating massive genetic diversity
Escape from CD8+ T cell and antibody responses by mutating epitopes
Downregulation of MHC class I by the Nef protein (reducing CD8+ T cell recognition)
Progressive depletion of the very cells (CD4+ T helpers) needed to sustain immune responses
Latency in resting memory cells renders the virus invisible to the immune system

Clinical Summary: CD4 Count and Risk

CD4+ Count	Clinical Status
>500 cells/µL	Normal immunity
200-500 cells/µL	Moderate immune suppression; some OI risk
<200 cells/µL	AIDS; high OI risk (PCP, etc.)
<100 cells/µL	Severe AIDS; CMV, MAC, cryptococcal risk
<50 cells/µL	Profound immunosuppression; CMV retinitis, disseminated MAC

Would you like to go deeper into any specific aspect - such as ART drug classes and mechanisms, opportunistic infections, diagnosis and staging, or HIV and the nervous system?

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