Human immunodeficiency virus

Epidemiology

Etiology

HIV is considered tropic for a certain cell type, depending on whether it preferentially binds to CCR5 or CXCR4 for viral entry, as follows:
- R5 virus uses CCR5 for viral entry and is considered macrophage-tropic because CCR5 is expressed in high concentrations on both macrophages and lymphocytes. R5 is the predominant HIV type (> 90%).
- X4 virus uses CXCR4 for viral entry and is considered T lymphotropic because CXCR4 is expressed primarily on T lymphocytes but only minimally on macrophages.
HIV trophism is determined by a gene sequence in the variable (V3) region of the env gene, which encodes for the HIV surface glycoprotein 120. This glycoprotein mediates viral attachment to the CD4 receptor and chemokine coreceptor.

Pathophysiology

Natural history of HIV infection

HIV enters the body (e.g., via mucosal lesions or via infection of mucosal/cutaneous immune cells.), then attaches to the CD4 receptor on host cells with its gp120 glycoprotein (binding)
- Cells that have CD4 receptors: T lymphocytes (e.g., T helper cells), macrophages, monocytes, dendritic cells.
Viral envelope fuses with host cell, capsid enters the cell.
- For fusion, CD4 receptor and a coreceptor (CCR5 in macrophages, and CCR5 or CXCR4 in T-cells) must be present.
- Viral entry into macrophages via CCR5 mainly occurs during the early stages of infection, while entry via CXCR4 occurs in later stages.
- Individuals without CCR5 receptors appear to be resistant to HIV, those patients either have a homozygous CCR5 mutation (substantial resistance) or a heterozygous CCR5 mutation (slower course).
A virion's RNA is transcribed into dsDNA by viral reverse transcriptase and then integrated into the host's DNA by viral integrase.
Viral DNA is replicated and virions are assembled
Virion repurposes a portion of the cell's membrane as an envelope and leaves the cell (budding) → cell death

Clinical features

Acute HIV infection

Also referred to as acute retroviral syndrome (ARS) or described as a mononucleosis-like syndrome
- Fever
- Fatigue
- Myalgia and arthralgia
- Headache
- Generalized nontender lymphadenopathy
- Generalized rash
- Gastrointestinal symptoms (nausea, diarrhea, weight loss)
- Oropharyngeal symptoms (sore throat, ulcerations, painful swallowing)

Tip

Acute retroviral syndrome is associated with extremely high levels of viral replication (~5 million copies/mL) as the cell-mediated and humoral antibody response against the virus is not yet fully activated.
Therefore, laboratory results during this period usually show evidence of HIV in the plasma (positive viral load and p24 antigen) with a negative serologic response (negative HIV-1/HIV-2 antibody).
This is referred to as the "window period," as patients are infected with HIV but HIV antibody screening tests may be negative (newer screening tests incorporate testing for HIV p24 antigen and are more sensitive in early infection).

AIDS-defining conditions

CD4+ cell count < 500/mm³

Kaposi sarcoma (typically occurs at CD4 count < 500)
Lymphoma
Mycobacterium tuberculosis

CD4+ cell count < 200/mm³

Pneumocystis pneumonia
Disseminated or extrapulmonary histoplasmosis
Progressive multifocal leukoencephalopathy

CD4+ cell count < 100/mm³

Cerebral toxoplasmosis
Extrapulmonary cryptococcosis (especially cryptococcal meningitis)
Cryptosporidiosis
- Etiology: Cryptosporidium species
- Clinical features: chronic, watery diarrhea (lasting > 1 month) with nausea and abdominal pains; typically at CD4 counts < 100
- Diagnostics: acid-fast oocysts in stool
Esophageal candidiasis or pulmonary candidiasis
- Oropharyngeal candida, which is not AIDS-defining, is more common as CD4 counts decline, and may be seen when CD4 count is < 200–250.
- Neutrophils are the most important immune cell in the defense against invasive Candida infection; therefore, patients with neutropenia (eg, following cytotoxic chemotherapy) are at high risk for invasive disease (eg, candidemia, meningitis). In contrast, T lymphocytes are more important for prevention of superficial, mucocutaneous infection (eg, thrush).
Primary CNS lymphoma
Disseminated and/or extrapulmonary Mycobacterium avium complex
Cytomegalovirus infection

CD4+ cell count < 50/mm³

Disseminated and/or extrapulmonary Mycobacterium avium complex
Cytomegalovirus infection
Aspergillosis
Primary CNS Lymphoma (PCNSL)

Neurological complications

HIV-associated neurocognitive disorder (HAND)

Definition: neurocognitive impairment in patients with HIV that cannot be attributed to a cause other than HIV infection. HAND is typically a diagnosis of exclusion.
Etiology: thought to result from a combination of dissemination of HIV into the CNS and the resultant immune activation.
Epidemiology: common even in patients with well-controlled HIV (affecting up to 50% of individuals)
Clinical features
- Early: mild impairment in attention, recall, and executive function
- Advanced: HIV-associated dementia (considered an AIDS-defining condition)
  - Subcortical dementia: memory loss, depression, movement disorders, behavioral changes (e.g., apathy)
  - Severe neurologic deficits: altered mental state, aphasia, gait disturbances
  - More common in patients with advanced or untreated HIV
Diagnostics
- Imaging: CT or MRI brain without and with IV contrast
  - Diffuse cerebral atrophy; disproportionate to the patient's age
  - Patchy symmetrical changes in the periventricular and deep white matter
  - No mass effect, no contrast-enhancement
- Histopathology shows giant cells with multiple nuclei (formed through fusion of HIV-infected monocytes).

Diagnostics

Serological assays

HIV antibody assays (i.e., third-generation and below): Detect IgM and IgG antibodies.
- Laboratory methods
  - Enzyme-linked immunosorbent assays (ELISA)
  - HIV-1 and HIV-2 antibody differentiation immunoassay
    - Laboratory-based test that can differentiate between HIV-1 and HIV-2 (provides separate results for each analyte)
    - Most commonly used confirmatory test in the US
  - Western blot: Detects only IgG antibody to HIV-1
Combination HIV antibody with HIV antigen test (i.e., fourth-generation and above): Can detect HIV IgG and IgM antibodies and p24 antigen.
- Cannot differentiate between HIV-1 and HIV-2 infection

Treatment

See HIV therapy

HIV in pregnancy

The transmission risk depends on maternal viral load.
Combined antiretroviral therapy (cART) is recommended throughout pregnancy and delivery. See HIV therapy#ART regimens
- In untreated individuals, rates of vertical transmission are as high as 30%. Effective maternal cART and neonatal zidovudine therapy can reduce the risk of perinatal HIV transmission to < 2%.