15.7 Viruses: HIV & Human Herpesvirus

Human Immunodeficiency Virus (HIV)

HIV is the cause of acquired immunodeficiency syndrome (AIDS). Two types exist: HIV-1 (global pandemic, more virulent) and HIV-2 (West Africa, slower course). The PA-CAT Bulletin of Information, rev. 20240815, places HIV within the Viruses group of the Microbiology blueprint. Understanding HIV structure and lifecycle is the foundation for both pathology questions and antiretroviral pharmacology.

Structure

HIV is an enveloped (+)ssRNA retrovirus with a diploid genome — two identical copies of ~9.7 kb RNA — packaged with three key enzymes:

• Reverse transcriptase (RT) — RNA-dependent DNA polymerase (lacks proofreading, hence high mutation rate).
• Integrase — inserts viral dsDNA into host chromosomes.
• Protease — cleaves polyproteins (Gag-Pol) into mature virion components.

The envelope contains gp120 (surface, binds receptor) and gp41 (transmembrane, mediates fusion), derived by cleavage of gp160 by host furin. The matrix protein (p17) lines the inner envelope; the capsid (p24, the major core antigen detected in fourth-generation tests) encases the RNA–enzyme complex.

Receptors and Cell Tropism

HIV binds CD4 on helper T cells, macrophages, and dendritic cells, then engages a co-receptor:

• CCR5 — used by M-tropic (R5) strains, dominant early in infection and in mucosal transmission. People homozygous for the CCR5-Δ32 deletion are largely resistant to HIV infection.
• CXCR4 — used by T-tropic (X4) strains, often emerging later and associated with rapid CD4 decline.

A key clinical corollary: maraviroc is a CCR5 antagonist effective only against R5-tropic virus (requires tropism testing).

HIV Replication Lifecycle

1. Attachment — gp120 binds CD4, conformational change exposes co-receptor binding site.
2. Co-receptor binding (CCR5 or CXCR4) triggers gp41 fusion.
3. Fusion and entry — viral core is released into cytoplasm.
4. Uncoating — capsid disassembles, releasing RNA–enzyme complex.
5. Reverse transcription — RT synthesizes a complementary DNA strand, degrades RNA (RNase H), and synthesizes the second DNA strand, producing dsDNA.
6. Nuclear import — the pre-integration complex enters the nucleus (HIV can infect non-dividing cells because integrase and matrix contain nuclear localization signals).
7. Integration — integrase cuts host DNA and ligates viral dsDNA, forming the provirus. This integrated form is the barrier to cure because it persists in latent reservoirs.
8. Transcription and splicing — host RNA polymerase II transcribes viral RNA; Rev protein exports unspliced and singly spliced RNAs.
9. Translation — Gag and Gag-Pol polyproteins (from unspliced RNA), Env (from spliced mRNA).
10. Assembly — virions bud from the plasma membrane.
11. Maturation — protease cleaves Gag-Pol into functional proteins; immature non-infectious particles become infectious. Protease inhibitors block this step.

Diagnosis

Modern algorithms start with a fourth-generation antigen/antibody combination assay (detects p24 antigen and anti-HIV-1/2 antibodies), narrowing the window period to ~18–45 days. Reactive results are confirmed with an HIV-1/HIV-2 differentiation immunoassay. Nucleic acid tests (HIV RNA) diagnose acute infection before seroconversion and quantify viral load for monitoring.

Stages of HIV Infection

AIDS-Defining Opportunistic Infections

AIDS-defining malignancies include Kaposi sarcoma (HHV-8), primary CNS lymphoma and systemic non-Hodgkin lymphoma (EBV-related), and invasive cervical carcinoma (HPV).

Antiretroviral Therapy (ART)

First-line ART combines two NRTIs (tenofovir + emtricitabine, or abacavir + lamivudine) with an integrase strand-transfer inhibitor (INSTI) — dolutegravir, bictegravir, or raltegravir. Drug classes target each lifecycle step:

ART suppresses viral load to undetectable (<200 copies/mL), restores CD4 counts, prevents transmission (U=U), and prevents drug resistance when adherence is high. Pre-exposure prophylaxis (PrEP) with tenofovir/emtricitabine reduces sexual acquisition by ~99%.

Human Herpesviruses

The Herpesviridae are enveloped, dsDNA viruses with an icosahedral capsid and a tegument layer. A defining property is latency: after primary infection, viral genomes persist in neurons (HSV-1/2, VZV) or B cells/monocytes (EBV, CMV, HHV-6/7) and reactivate under stress, immunosuppression, or UV light. Eight human herpesviruses are recognized:

HSV-1 and HSV-2

Herpes simplex viruses produce vesicular lesions on an erythematous base. Primary infection is usually more severe than reactivation. HSV-1 classically causes orolabial lesions ('cold sores') and increasingly genital herpes; HSV-2 predominantly causes genital herpes. Reactivation triggers include UV light, fever, stress, and menstruation. Genital HSV can be transmitted even without visible lesions (asymptomatic shedding).

Diagnosis: PCR of lesion swab (gold standard) or CSF (HSV encephalitis — temporal lobe predilection); Tzanck smear shows multinucleated giant cells with eosinophilic intranuclear inclusions (Cowdry type A) but is less sensitive. Treatment: acyclovir, valacyclovir, or famciclovir; suppressive therapy reduces recurrences and transmission. Acyclovir requires viral thymidine kinase to phosphorylate it to the active form, so it has minimal host toxicity but is inactive against CMV (which lacks TK).

VZV — Chickenpox and Shingles

Primary VZV causes varicella (chickenpox): fever and a pruritic vesicular rash in crops that progresses from macules → papules → vesicles → pustules → crusts, starting on the trunk and spreading peripherally. The virus then establishes latency in dorsal root ganglia. Reactivation produces herpes zoster (shingles): a painful vesicular eruption in a single dermatome (thoracic and lumbar most common; ophthalmic branch of V1 in herpes zoster ophthalmicus). Post-herpetic neuralgia is the most common complication.

The varicella vaccine (live attenuated) prevents primary disease; the shingles vaccine (recombinant zoster vaccine, RZV) prevents reactivation and post-herpetic neuralgia, recommended for adults ≥50. Antivirals (acyclovir, valacyclovir, famciclovir) are most effective when started within 72 hours of rash onset.

EBV — Infectious Mononucleosis

EBV infects B cells via CD21 (CR2) and establishes latency. Infectious mononucleosis presents with fever, exudative pharyngitis, lymphadenopathy (especially posterior cervical), and fatigue, often with splenomegaly (avoid contact sports to prevent splenic rupture). Atypical Downey lymphocytes on smear are reactive cytotoxic T cells, not EBV-infected B cells.

Heterophile antibody (Monospot) agglutinates horse/sheep RBCs; it is positive in ~90% of adults but less sensitive in young children. EBV-specific serology (VCA IgM, EBNA IgG) clarifies ambiguous cases. EBV is also associated with African Burkitt lymphoma (t(8;14) c-myc translocation), nasopharyngeal carcinoma, Hodgkin lymphoma, and post-transplant lymphoproliferative disorder (PTLD).

CMV

CMV causes the 'CMV mononucleosis' syndrome that is heterophile-negative and often presents with fever and mild hepatitis; petechial rash may follow ampicillin administration (similar to EBV). In immunocompromised hosts, CMV causes retinitis (AIDS with CD4 <50 — 'pizza-pie' fundus), colitis with ulceration, esophagitis, pneumonitis (transplant recipients), and encephalitis. Congenital CMV is the most common congenital infection in the U.S. — sensorineural hearing loss, petechiae ('blueberry muffin' rash from dermal extramedullary hematopoiesis), chorioretinitis, and periventricular calcifications.

Treatment: ganciclovir, valganciclovir, foscarnet, or cidofovir (not acyclovir — CMV lacks TK; ganciclovir is phosphorylated by the UL97 kinase). Letermovir (CMV terminase inhibitor) is used for prophylaxis in stem-cell transplant recipients.

HHV-6 — Roseola Infantum

HHV-6B causes roseola (exanthem subitum, sixth disease): high fever for 3–5 days in an otherwise well-appearing infant, followed by defervescence and a maculopapular rash that appears as fever drops. Febrile seizures are a feared complication. The rash starts on the trunk and spreads to the face and extremities.

HHV-8 — Kaposi Sarcoma

HHV-8 (KSHV) is the causative agent of Kaposi sarcoma, an angioproliferative tumor classically seen in AIDS patients (especially MSM) but also in classic (Mediterranean/Eastern European elderly men), endemic (sub-Saharan Africa), and transplant-associated forms. Lesions are violaceous plaques and nodules on skin, oral mucosa, GI tract, and lungs.

HIV and Herpesviruses: Key Interactions

• EBV-driven primary CNS lymphoma and HHV-8 Kaposi sarcoma are AIDS-defining malignancies.
• CMV retinitis and chronic progressive VZV (zoster that disseminates) are classic late-stage opportunistic diseases.
• HSV reactivation is common at any CD4 count but more severe with immunosuppression.
• ART-induced immune reconstitution inflammatory syndrome (IRIS) can unmask occult herpesvirus disease (e.g., CMV retinitis, VZV uveitis) within weeks of starting therapy.