Viral Infections in Acquired Immunodeficiency Syndrome

Acquired immunodeficiency syndrome (AIDS) is the late stage of untreated human immunodeficiency virus (HIV) infection, and it is one of the most important acquired causes of immunocompromise worldwide. The defect it produces is a progressive loss of CD4 T-cell help and cell-mediated immunity, which is precisely the arm of the immune system that contains the latent herpesviruses, the polyomaviruses, and the oncogenic viruses. As that immunity fails, these viruses reactivate and cause disease in a predictable, CD4-dependent order. The diseases that follow, rather than the diagnosis or antiretroviral management of HIV itself, are the subject here.

How HIV leads to AIDS

HIV is a retrovirus that infects and depletes CD4 T lymphocytes. Productive infection occurs mainly in activated CD4 cells, which die within a day or two, but direct killing alone cannot explain the loss of the whole CD4 compartment. Several mechanisms act together: direct cytopathic killing of infected cells; syncytium formation, in which the viral envelope fuses an infected cell to uninfected neighbours (more pronounced with the CXCR4-using strains that emerge late and accelerate decline); and, most importantly, chronic immune activation. The trigger for that activation is an early, massive depletion of CD4 cells from the gut-associated lymphoid tissue, which breaches the mucosal barrier and allows microbial translocation: bacterial products entering the circulation drive persistent inflammation and interferon signalling. The CD8 cytotoxic T cells that initially control the virus become exhausted, and lymphoid tissue becomes fibrotic. The result is a steady erosion of cell-mediated immunity.

Untreated, the CD4 count falls by around 50 to 100 cells per microlitre each year, faster when the viral set point is high. The infection passes through an acute, mononucleosis-like illness with very high viraemia, a long and largely asymptomatic phase of gradual CD4 decline, and finally clinical immunodeficiency, on average eight to ten years from infection.

AIDS is defined by a CD4 count below 200 cells per microlitre (or below 14 per cent of lymphocytes), or by the occurrence of an AIDS-defining condition at any count. Several of those conditions are themselves viral: cytomegalovirus end-organ disease, chronic herpes simplex ulceration, Kaposi sarcoma, the aggressive B-cell and primary central nervous system lymphomas, progressive multifocal leukoencephalopathy, and invasive cervical cancer.

The CD4 count and viral susceptibility

The CD4 count is the central predictor of viral disease in HIV. As it falls, cell-mediated control of the latent viruses fails in a recognisable sequence, so the count both anticipates which infection to expect and frames how aggressively to treat and monitor.

CD4 (cells per microlitre)	Viral infections that emerge
Below 350	Herpes zoster (varicella-zoster virus); more frequent and severe mucocutaneous herpes simplex
Below 200 (AIDS)	Multidermatomal or disseminated varicella-zoster; oral hairy leukoplakia
Below 100	Chronic or visceral herpes simplex; EBV-driven systemic non-Hodgkin lymphoma; progressive multifocal leukoencephalopathy (JC virus)
Below 50	Cytomegalovirus end-organ disease (retinitis, colitis and others); EBV-driven primary central nervous system lymphoma

Two viral problems sit outside this ladder. Kaposi sarcoma (HHV-8) and HPV-related cancers occur across a wide range of counts, though advanced disease is commoner at low counts, and hepatitis B is governed by coinfection and the depth of immunosuppression rather than by a CD4 threshold. The thresholds are a guide; disease can present outside its usual band.

The viruses

Virus	Hallmark disease in AIDS	Typical CD4	Management anchor
Herpes simplex virus	Chronic, extensive or visceral mucocutaneous ulceration	Below 100	Aciclovir family; antiretroviral therapy
Varicella-zoster virus	Multidermatomal or disseminated zoster; vasculopathy, encephalitis	Below 200 to 350	Aciclovir family; antiretroviral therapy
Cytomegalovirus	Retinitis, colitis, oesophagitis, pneumonitis, encephalitis	Below 50	Valganciclovir or ganciclovir; antiretroviral therapy
Epstein-Barr virus	Oral hairy leukoplakia; non-Hodgkin and primary CNS lymphoma	Below 100 (lymphoma)	Antiretroviral therapy; chemotherapy for lymphoma
HHV-8 (KSHV)	Kaposi sarcoma; primary effusion lymphoma; Castleman disease	Variable	Antiretroviral therapy; chemotherapy for advanced disease
JC polyomavirus	Progressive multifocal leukoencephalopathy	Below 100	Antiretroviral therapy (no specific antiviral)
Human papillomavirus	Extensive warts; cervical and anal cancer	Variable	Screening; antiretroviral therapy; lesion-directed treatment
Hepatitis B virus	Accelerated liver disease; reactivation	Coinfection	Tenofovir-based antiretroviral therapy covering both

Herpesviruses

Five human herpesviruses cause the bulk of viral disease in AIDS. All establish lifelong latency and are held in check by CD4-dependent cell-mediated immunity, so all re-emerge as that immunity is lost. They differ in the CD4 level at which they declare themselves and in the organs they damage.

Herpes simplex virus

In advanced HIV, herpes simplex becomes more frequent, more severe and slower to heal. Orolabial and anogenital lesions may form deep, enlarging or chronic ulcers persisting beyond a month, which is an AIDS-defining condition, and disease may extend to the oesophagus, trachea or lung. Chronic and visceral disease typically appears below a CD4 count of 100. The main burden is painful, non-healing ulceration rather than high mortality, though aciclovir resistance (through viral thymidine-kinase mutations) emerges with prolonged drug exposure and complicates treatment. The diagnosis is confirmed by PCR of a swab from the base of a lesion, with viral culture able to provide isolates for resistance testing and biopsy reserved for atypical or visceral disease. Management is with aciclovir, valaciclovir or famciclovir, intravenous aciclovir for severe or visceral disease, and foscarnet for resistant disease; antiretroviral therapy restores control, and suppressive therapy is used for frequent recurrences.

Varicella-zoster virus

Reactivation as herpes zoster (shingles) occurs at a relatively high CD4 count, with risk rising below 350, and zoster in a young adult is often the first clue to undiagnosed HIV. As immunity falls further, zoster becomes multidermatomal or disseminated, and visceral and neurological disease appears: encephalitis, myelitis, a progressive outer retinal necrosis that rapidly blinds, and a vasculopathy that can cause stroke. Primary varicella in a seronegative adult can disseminate to the lungs. Disseminated and visceral disease is typically seen below a CD4 count of 200 and carries significant mortality. The diagnosis is usually clinical, confirmed where needed by PCR of vesicle fluid or, in central nervous system disease, of cerebrospinal fluid. Treatment is with aciclovir or valaciclovir, given intravenously for disseminated, ophthalmic, visceral or central nervous system disease, alongside antiretroviral therapy. A non-immune patient exposed to varicella or zoster is given varicella-zoster immunoglobulin; the non-live recombinant zoster vaccine is used where available, and live vaccines are avoided in severe immunosuppression.

Cytomegalovirus

Cytomegalovirus is the classic very-late opportunistic infection, appearing below a CD4 count of 50. Retinitis is the commonest and most characteristic manifestation. On dilated fundoscopy it produces well-demarcated areas of full-thickness retinal necrosis, seen as fluffy or granular white opacification that spreads along the retinal vessels and is accompanied by retinal haemorrhages, with characteristically little vitreous inflammation given the low CD4 count. It begins peripherally with floaters and field loss and threatens sight as it advances towards the macula or optic disc; untreated it progresses to blindness, and retinal detachment is a feared late complication. Other forms are colitis (diarrhoea, abdominal pain, bleeding), oesophagitis, pneumonitis, and encephalitis or ventriculitis with cognitive decline and somnolence. End-organ disease raises mortality, and the visual prognosis is guarded once the macula is involved or the retina detaches.

Retinitis is a clinical diagnosis made on dilated fundoscopy by an experienced examiner, since the appearance is characteristic; organ disease is confirmed on biopsy, which shows enlarged cells bearing intranuclear “owl’s-eye” inclusions, supported by immunohistochemistry. The blood viral load supports the diagnosis and tracks the response but is often low in compartmentalised disease such as retinitis. Treatment is with systemic valganciclovir or ganciclovir, given as induction then maintenance until immune recovery (a sustained CD4 count above 100), with foscarnet or cidofovir as alternatives and intravitreal therapy for immediately sight-threatening retinitis. Antiretroviral therapy is essential, since durable control depends on restoring immunity.

Epstein-Barr virus

Epstein-Barr virus produces a spectrum from benign to malignant. Increased oropharyngeal shedding is common, and oral hairy leukoplakia, corrugated white plaques on the lateral border of the tongue that do not rub off, is a harmless but useful clinical marker of immunosuppression; it needs no specific treatment and regresses with immune recovery.

The serious manifestations are the EBV-driven lymphomas, which arise as failing T-cell immunity allows EBV-infected B cells to proliferate. Systemic non-Hodgkin lymphoma is usually a high-grade B-cell tumour: diffuse large B-cell (immunoblastic and centroblastic), Burkitt, and plasmablastic lymphoma (characteristically of the oral cavity and jaw). These present across a range of CD4 counts, often with advanced-stage, extranodal and B-symptom disease, and are staged and treated as aggressive lymphomas with chemotherapy (anthracycline-based regimens, with rituximab for CD20-positive disease) given alongside antiretroviral therapy; outcomes have improved substantially in the antiretroviral era.

Primary central nervous system lymphoma is a later complication, usually below a CD4 count of 50, and is almost always EBV-positive. It presents with focal neurological deficits, seizures or altered mental status, and appears on imaging as one or more contrast-enhancing mass lesions, often periventricular. The principal differential is cerebral toxoplasmosis, and the two are separated by EBV DNA PCR in cerebrospinal fluid (positive in lymphoma), by metabolic imaging (the lymphoma is hypermetabolic on positron emission tomography or thallium single-photon emission tomography, whereas toxoplasmosis is not), and, where doubt remains, by brain biopsy. The prognosis is poor, and treatment combines high-dose methotrexate-based therapy with antiretroviral therapy. Antiretroviral therapy is central to all of these lymphomas, restoring the T-cell control that antivirals cannot provide, since the latent virus offers them no target.

Human herpesvirus 8

Human herpesvirus 8, the Kaposi sarcoma-associated herpesvirus, causes Kaposi sarcoma, primary effusion lymphoma and multicentric Castleman disease. Kaposi sarcoma presents as violaceous patches, plaques and nodules on the skin and mucosa, characteristically on the palate and gingiva, and may involve the gastrointestinal tract and lungs, where it can bleed or obstruct. The AIDS-associated form is the most aggressive type of Kaposi sarcoma. It is not tightly linked to a CD4 threshold, though advanced disease is commoner at low counts, and visceral or pulmonary disease carries substantial mortality. Extent is described by the AIDS Clinical Trials Group staging (by tumour, immune status and systemic illness), which guides treatment.

Antiretroviral therapy is the mainstay and often suffices alone: restoring immune control of HHV-8 causes many limited cutaneous lesions to regress without specific cancer treatment, so it is first-line for limited disease. Advanced, visceral or rapidly progressive disease needs systemic chemotherapy (liposomal anthracyclines, or paclitaxel) alongside antiretroviral therapy, with local treatment for troublesome individual lesions. A particular caution is Kaposi-sarcoma immune reconstitution, in which lesions flare as immunity recovers in the early months of therapy. Diagnosis is by biopsy, showing spindle cells and slit-like vascular spaces and confirmed by LANA-1 immunostaining for HHV-8, although in high-prevalence settings the clinical appearance often guides initial treatment while histology is awaited.

JC polyomavirus and progressive multifocal leukoencephalopathy

The JC polyomavirus reactivates in advanced HIV to cause progressive multifocal leukoencephalopathy (PML), a demyelinating disease in which the virus destroys oligodendrocytes. It presents subacutely, below a CD4 count of 100, with focal deficits (hemiparesis, visual field loss, aphasia, ataxia, hemisensory loss) and cognitive change over days to weeks, which distinguishes it from the more global, behavioural picture of HIV-associated dementia. The prognosis is poor: historically rapidly fatal, and even with treatment the one-year mortality is around 30 to 50 per cent, with residual neurological deficits in survivors. There is no specific antiviral; prompt antiretroviral therapy to achieve immune reconstitution is the only effective intervention and the principal determinant of survival. The diagnosis rests on a characteristic magnetic resonance imaging appearance: multifocal, asymmetric white-matter lesions that are hyperintense on T2 and FLAIR sequences, typically subcortical and extending into the subcortical U-fibres, without mass effect and with little or no contrast enhancement (enhancement, when present, suggests an immune-reconstitution reaction). It is confirmed by JC virus PCR in cerebrospinal fluid, which is highly specific but imperfectly sensitive, so a negative result does not exclude the diagnosis; brain biopsy is reserved for unresolved doubt.

Human papillomavirus

Human papillomavirus disease becomes more extensive and harder to treat as immunity falls. Cutaneous and anogenital warts are larger, more numerous and more refractory, and, more importantly, cervical and anal intraepithelial neoplasia progresses faster, giving a several-fold higher risk of invasive cervical cancer (an AIDS-defining condition) and anal cancer. Oropharyngeal disease also occurs. Risk tracks the duration and depth of immunosuppression rather than a single CD4 threshold. The cornerstone of care is regular cervical screening (and anal screening where indicated), since early dysplasia is treatable; abnormal cytology is investigated by colposcopy or high-resolution anoscopy with biopsy. This sits alongside antiretroviral therapy and lesion-directed or oncological treatment of established disease. The HPV vaccine is non-live and safe in HIV, and is given to eligible patients.

Hepatitis B virus

HIV and hepatitis B share transmission routes, so coinfection is common, and HIV worsens the course of hepatitis B: fibrosis progresses faster, chronic infection is more likely, and reactivation occurs as immunosuppression deepens or with B-cell-depleting therapy. Coinfection is governed by the two viruses and the depth of immunosuppression rather than by a CD4 threshold, and it carries accelerated cirrhosis and higher liver-related mortality. The central management point is that the antiretroviral regimen must include agents with anti-hepatitis-B activity, namely tenofovir with emtricitabine or lamivudine, so that both viruses are treated; a regimen that suppresses hepatitis B with a single agent risks selecting resistance, and stopping such a drug can provoke a hepatitis flare. Every patient with HIV is screened for hepatitis B and the non-immune are vaccinated, and a hepatic flare is watched for when antiretroviral therapy begins.

Immune reconstitution inflammatory syndrome

Restoring immunity with antiretroviral therapy can itself precipitate disease. Immune reconstitution inflammatory syndrome (IRIS) is a paradoxical clinical deterioration driven by the recovering immune response, not by failure of treatment or by drug toxicity. It takes two forms: a paradoxical worsening of an opportunistic infection that was already known and being treated, and an unmasking of an infection that was previously occult. The risk is greatest when antiretroviral therapy is started at a very low CD4 count, with a high HIV viral load, a high pathogen burden, and a short interval between treating the infection and starting therapy.

Several viral infections are important causes. Cytomegalovirus can produce an immune-recovery uveitis or retinitis that threatens vision even as the systemic infection improves. PML can flare into a PML-IRIS that is sometimes fulminant, with cerebral oedema. Kaposi sarcoma can worsen abruptly as a KS-IRIS, and zoster commonly appears or flares in the first weeks of therapy.

The timing of antiretroviral therapy balances the benefit of immune recovery against the risk of inflammation in a confined space. For most opportunistic infections therapy is started early, within about two weeks. The clearest exceptions are tuberculous and cryptococcal meningitis, where therapy is delayed by several weeks to reduce dangerous central nervous system inflammation; although these are not viral, they establish the principle. PML is the opposite case: therapy should not be delayed, because immune recovery is the only effective treatment. When IRIS occurs, both antiretroviral therapy and infection-specific treatment are continued, with corticosteroids for severe inflammatory manifestations such as cerebral PML-IRIS or sight-threatening uveitis; interrupting antiretroviral therapy is rarely necessary.

Prevention and the role of antiretroviral therapy

Antiretroviral therapy is the single most effective measure against viral opportunistic infection, because restoring the CD4 count reverses the underlying susceptibility. The incidence of opportunistic infection fell sharply once effective therapy became available, and AIDS-related death has declined accordingly.

Unlike the non-viral opportunistic infections, where prophylaxis is established (co-trimoxazole against Pneumocystis and Toxoplasma), the viral infections are generally not prevented by routine antiviral prophylaxis. There is no routine prophylaxis against cytomegalovirus, herpes simplex, varicella-zoster, HHV-8 or JC virus. The approach instead is early antiretroviral therapy, patient education (in particular prompt reporting of visual symptoms at very low CD4 counts), and targeted screening: ophthalmological review for those with the lowest counts, and cervical and anal cytology for HPV-related disease. Vaccination contributes where the vaccine is non-live: hepatitis B and HPV vaccines are recommended, and the recombinant zoster vaccine is used where available.

A point of currency: decisions about when to start antiretroviral therapy were once tied to the CD4 count, but universal treatment at diagnosis has superseded that. The CD4 count now indicates which infections to anticipate and when to add specific screening or prophylaxis, not whether to treat HIV.

South African context

Advanced HIV disease remains common in South Africa despite one of the largest antiretroviral programmes in the world, because of late presentation and treatment interruption. Clinicians therefore still see the classic late picture of cytomegalovirus retinitis, progressive multifocal leukoencephalopathy and Kaposi sarcoma, and early mortality after presentation with advanced disease is high. HHV-8 is endemic, with adult seroprevalence exceeding 50 per cent in parts of sub-Saharan Africa, so Kaposi sarcoma is among the commonest cancers in the region; in high-burden settings the clinical appearance often guides initial treatment while biopsy and LANA-1 confirmation are awaited. Resource considerations shape practice: cytomegalovirus is managed with valganciclovir and ganciclovir, since newer agents such as letermovir are not generally available, and the recombinant zoster vaccine is not widely accessible. The National Health Laboratory Service provides the quantitative PCR and CD4 testing that underpin diagnosis and monitoring. (This section is a general orientation and would be strengthened by a current local protocol.)

References and recommended reading

• Richman DD, Whitley RJ, Hayden FG (eds.). Clinical Virology, 4th edition, Chapter 34 (advanced HIV and AIDS). Washington: ASM Press; 2016. Immunopathogenesis, natural history and the CD4 thresholds of opportunistic infection.
• HIV-1-Associated Opportunistic Infections. StatPearls (NCBI Bookshelf). Treasure Island: StatPearls Publishing; accessed June 2026. Clinical presentation, diagnosis, treatment and immune reconstitution inflammatory syndrome of the individual infections.
• UpToDate (Wolters Kluwer): AIDS-defining conditions; and Overview of prevention of opportunistic infections in patients with HIV. Accessed June 2026. The AIDS-defining condition list and the prophylaxis and screening framework (paraphrased).
• Bekker L-G, Beyrer C, Mgodi N, et al. HIV infection. Nature Reviews Disease Primers 2023;9:42. DOI 10.1038/s41572-023-00452-3. Microbial translocation, immune activation, CD8 exhaustion and the rate of CD4 decline.