Infection with the human immunodeficiency virus (HIV) leads to a complex disease pattern which ultimately results in chronic immunodeficiency. HIV can be transmitted sexually, parenterally, or vertically (e.g., peripartum from mother to child). Infection is most common in the young adult population between 20 and 30 years of age. The virus infects macrophages and other CD4+ cells, leading to the destruction of CD4 T cells and thereby impairing one of the key mechanisms of cellular immune defense. There are three major stages: acute infection, clinical latency, and acquired immunodeficiency syndrome (AIDS). For clinical staging, detailed classifications have been established by the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO). During the stage of acute infection, the virus reproduces rapidly in the body, which can lead to acute, nonspecific (e.g., flu-like) symptoms (also known as acute retroviral syndrome, ARS) within 2–4 weeks. However, approximately half of all infected individuals remain asymptomatic. Once the stage of acute infection subsides, the clinical latency stage begins. Again, many individuals remain asymptomatic during this period, while others develop non-AIDS-defining conditions (e.g., oral hairy leukoplakia). The last stage, AIDS, is characterized by AIDS-defining conditions (e.g., Kaposi sarcoma) and/or a CD4 count < 200 cells/mm3. HIV infection can reliably be detected via antigen/antibody-based tests. In patients with confirmed infection, the most important parameters for monitoring the disease are CD4 count and viral load. HIV treatment involves a combination of antiretroviral drugs (combination antiretroviral therapy, cART). In addition, HIV-related complications (e.g., HIV wasting syndrome, opportunistic infections) will require management. There have been significant advances in treatment so that the average life expectancy of HIV patients receiving current antiretroviral drugs is approaching that of the general population.
- Incidence (in the US)
- US: ∼ 1.2 million
- Global: ∼ 37 million
Epidemiological data refers to the US, unless otherwise specified.
Pathogen (human immunodeficiency virus)
- Family: Retroviridae
- Genus: Lentivirus
- HIV-1: most common species worldwide
- HIV-2: restricted almost completely to West Africa
- Structure: icosahedral with a conical capsid and a spiked envelope
Function of structural proteins
- pol gene codes for a polyprotein which consists of
- gag gene codes for gag protein, which consists of
- env gene codes for gp160 which gets cleaved into envelope glycoproteins
- tat gene (trans-activator of transcription) codes for tat protein which promotes viral transcription
Routes of transmission
Sexual: responsible for ∼ 80% of infections worldwide
- Risk per sexual act
- Modifying factors
- Viral load: studies have shown that transmission is unlikely if viral load is < 400 copies/ml 
- Circumcision: reduced risk of infection for circumcised men 
- Coinfection: genital inflammation (e.g., as a result of coinfection with other pathogens such as HPV or genital herpes) increases local virus concentration and therefore risk of transmission
- Genital mucosal damage: increases risk of transmission
- Parenteral transmission
- Vertical transmission: from mother to child
Risk of transmission can be lowered significantly if HIV infection is treated consistently and viral load is below the limit of detection!
Natural history of HIV infection
Initial infection and HIV replication cycle
- 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)
- 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 
Progression to chronic immunodeficiency
- HIV infects CD4+ lymphocytes, then reproduces and spreads to other CD4+ lymphocytes near the original site of infection → infection of CD4+ lymphocytes concentrated in specialized lymphoid tissue (e.g., lymph nodes or gut-associated lymphatic tissue (GALT) ) → explosive growth and dissemination → acute HIV syndrome with high viral load
- After the acute stage, viral load decreases and remains at roughly that level for approximately 8–10 years (clinical latency stage ).
- During the clinical latency phase, the virus mainly replicates inside the lymph nodes.
- Increasing loss of CD4+ lymphocytes (especially T cells) impairs immune function and, thereby, facilitates opportunistic infections and development of malignancies (AIDS). These secondary diseases are usually the cause of death in individuals with HIV.
- Increased viral load generally leads to a decreased number of CD4+ lymphocytes and vice versa, but the relation is not linear.
Viral load predicts the rate of disease progression and CD4 count correlates with immune function.
Acute HIV syndrome does not develop in all patients. Absence of symptoms may delay diagnosis.
The role of immune response
- Because HIV infects cells of the immune system itself, activation of cellular immunity is a factor that paradoxically helps the virus spread and ensures chronic persistence of the infection.
- HIV evades immune control via:
- Genetic mutation and recombination
- Downregulation of surface molecules in infected cells
- There are no clinical features specific to HIV infection
- In early HIV infection, patients are often asymptomatic.
- Incubation period: usually 2–4 weeks 
- Infectiousness: two peaks (1st peak: within the first months after infection; 2nd peak: during AIDS-stage)
Acute HIV infection 
- Also referred to as acute retroviral syndrome (ARS) or described as a mononucleosis-like syndrome.
- Myalgia and arthralgia
- Generalized nontender lymphadenopathy
- Generalized rash
- Gastrointestinal symptoms (nausea, diarrhea, weight loss)
- Oropharyngeal symptoms; (sore throat, ulcerations, painful swallowing)
Clinical latency and AIDS
- Clinical latency: Infected individuals may still be asymptomatic.
Non-AIDS-defining conditions (common when CD4+ count is below 500 cells/mm3)
- Chronic subfebrile temperatures
- Persistent generalized lymphadenopathy
- Chronic diarrhea (> 1 month)
- Localized opportunistic infections
- Oral hairy leukoplakia: lesions that cannot be scraped off located mainly on the lateral borders of the tongue; triggered by Epstein-Barr virus
- HPV-related: squamous cell carcinoma of the anus (common in men who have sex with men) or cervix
- Skin manifestations (e.g. molluscum contagiosum, warts; , exacerbations of psoriasis, shingles)
- AIDS: See article on “
Test patients with a history of intravenous drug use who present with otherwise unexplained weight loss, depression, and/or dementia for HIV.
CDC classification system for HIV 
- CDC categories of HIV are based on CD4 count in combination with current or previously diagnosed HIV-related conditions.
- Any patient belonging in categories A3, B3 or C1-C3 is considered to have AIDS.
| CD4 cell count category |
(normal cell count: 500-1500 cells/mm3)
Clinical category A
Asymptomatic, Acute HIV
Clinical category B
Clinical category C
|(1) ≥ 500 cells/mm3||A1||B1||C1|
|(2) 200–499 cells/mm3||A2||B2||C2|
|(3) < 200 cells/mm3||A3||B3||C3|
PGL= Persistent generalized lymphadenopathy
WHO (World Health Organization) classification 
WHO classifies individuals with confirmed HIV infection according to clinical features and diagnostic findings:
- Primary HIV infection: acute retroviral syndrome or asymptomatic
- Clinical stage 1: persistent generalized lymphadenopathy (PGL) or asymptomatic
- Clinical stage 2: e.g., unexplained moderate weight loss (< 10%), recurrent fungal/viral/bacterial infections
- Clinical stage 3: e.g., unexplained severe weight loss (> 10%), unexplained chronic diarrhea (> 1 month), unexplained persistent fever (≥ 37.6°C intermittent or constant > 1 month), persistent/severe fungal/viral/bacterial infections , unexplained anemia (< 8 g/dL) and/or neutropenia (< 500 cells/mm3) and/or chronic thrombocytopenia (< 50,000/μL) for more than 1 month
- Clinical stage 4: AIDS-defining conditions (e.g., Kaposi sarcoma, Pneumocystis pneumonia)
- Test all patients with clinical features of acute or chronic HIV infection
- All individuals with possible past exposure, especially high-risk individuals (e.g., sex workers, men who have sex with men, IV drug users, partners of HIV-positive individuals): regular testing (e.g., annually)
- One-time testing is recommended early in every pregnancy
- HIV-testing requires patient consent (opt-out)
Initial diagnostic approach 
Combination antigen/antibody tests (first-choice screening test)
- Detect both HIV antigen (p24 capsid protein) and anti-HIV antibodies (IgG antibodies against HIV-1/HIV-2) → a negative result essentially rules out HIV infection (almost 100% sensitivity)
- Not recommended for suspected neonatal HIV infection (results may be false-positive due to maternally transferred anti-HIV antibodies)
- Viral RNA load test should be done in case of suspicion of perinatal HIV infection
Antibody-only tests (HIV serology)
- ELISA (enzyme-linked immunosorbent assay): standard method for detecting antibodies within approx. 1–3 hours; requires laboratory
- Rapid tests: can deliver results in ∼ 20 minutes and do not require a laboratory, which makes them suitable as an alternative to the more complex tests in some outpatient settings.
- Combination antigen/antibody tests (first-choice screening test)
- HIV-1/HIV-2 antibody differentiation immunoassay; (first-choice confirmatory test): can detect both HIV-1 and HIV-2 in ∼ 20 minutes and distinguish between the two types
- Western blot:
- Detection of viral RNA
- HIV drug resistance testing 
- Viral RNA load: indicator of ART response
- CD4+ count: correlates with overall immune function
- CD4+:CD8+ ratio: Used in the immunological evaluation of long-term follow-up cases 
Additional laboratory studies
- CBC: possibly lymphocytopenia
- Liver enzymes: if abnormal, rule out coinfection with hepatitis virus (HCV or HBV)
General approach 
- All persons infected with HIV (regardless of CD4 count) should begin combined antiretroviral therapy (cART) as soon as possible
- Antiretroviral therapy should be prioritized in patients with:
- Therapy should be determined based on the HIV genotype
- Antiretroviral drugs are combined to prevent resistance (see “Regimens” below for details)
- All antiretroviral drugs are able to target both HIV-1 and HIV-2, except for enfuvirtide and NNRTIs
Antiretroviral drugs 
Nucleoside reverse transcriptase inhibitors (NRTI)
- Examples of drugs
Mechanism of action
- NRTIs act as nucleoside analogs → competitive blockage of nucleoside binding to reverse transcriptase → inhibition of formation of 3' to 5' phosphodiester linkages → termination of DNA chain → inhibition of RNA to DNA reverse transcription
- Activation requires intracellular phosphorylation, thus their efficacy is reliant on kinase availability and activity, which varies depending on cell functionality and activation state.
- Bone marrow suppression: anemia (especially zidovudine), neutropenia
- Mitochondrial toxicity
- Abacavir-related hypersensitivity syndrome 
- Pancreatitis (didanosine/stavudine)
- HIV-associated lipodystrophy (Cushing-like syndrome): abnormal distribution of fat
Tenofovir: nephrotoxicity 
- Studies link tenofovir to proximal tubular dysfunction, acute tubular necrosis, and subsequent acute kidney injury.
- Affected individuals show elevated creatinine, subnephrotic proteinuria, and glycosuria.
- Acute tubular necrosis was confirmed via renal biopsy, which revealed enlarged, depleted, and dysmorphic mitochondria.
- Discontinuation lead to significant recovery and suggests reversibility of the toxic tenofovir effects.
- Resistance: caused by mutations in the gene that codes for reverse transcriptase (pol gene)
Nonnucleoside reverse-transcriptase inhibitors (NNRTI)
Examples of drugs
- Mechanism of action
- Side effects
HIV protease inhibitors (PI)
Examples of drugs
- Mechanism of action: inhibition of viral HIV-1 protease (encoded by pol gene) → inability to cleave viral mRNA into functional units → generation of impaired viral proteins → production of immature (noninfectious) virions
- Side effects
- Special indications: Ritonavir can be used to increase concentrations of other drugs since it inhibits cytochrome P450.
Integrase inhibitors (INI)
Examples of drugs
- Mechanism of action: inhibition of the viral integrase → blockade of viral DNA integration into the host's DNA → inhibition of viral replication
- Side effects: ↑ creatine kinase
Entry inhibitors 
- Description: Hetereogenic class of antiretroviral drugs that inhibit binding or fusion of HIV virions with human cells.
Examples of drugs
- Enfuvirtide (fusion inhibitor)
- Maraviroc (CCR5-antagonist)
- Special indications : infection with drug-resistant HIV-1 
To remember the mechanism of action of maraviroc, think: “Maraviroc will block the viral dock.”
- Recommended regimens
- Combinations that should be avoided
- See the article on “.”
Immune reconstitution inflammatory syndrome
- Deterioriation of a preexisting opportunistic infection (e.g., PML, Kaposi sarcoma) within 60 days after initiation of HAART therapy
- Thought to be caused by the restoration of immune function that results in inflammatory reactions at previously dormant sites of infection.
- Occurs in 10–25% of patients with AIDS
We list the most important complications. The selection is not exhaustive.
Morbidity and mortality among patient subsets
- Untreated, HIV leads to death on average 8–10 years after infection.
- Progression varies among individuals: some patients may die within a few years while others remain asymptomatic for decades
- Untreated individuals with advanced HIV infection usually die within a few years (median survival is 12–18 months)
- The average life expectancy of HIV-infected individuals who receive adequate antiretroviral treatment is approaching that of noninfected individuals of the same age. 
- Individuals with HIV infection on adequate antiretroviral therapy are more likely to develop chronic comorbidities (e.g., cardiovascular disease, diabetes, cancer) than healthy individuals. 
- Individual prognosis depends on various factors, including:
HIV pre-exposure prophylaxis 
- Men who have sex with men
- Heterosexual men and women
- Intravenous drug users with high-risk needle behavior (e.g., sharing needles/equipment) or HIV positive injection partner
- Timing: Prior to the exposure to HIV and continued for a month after the exposure.
- HIV test every 3 months
- Renal assessment at baseline and every 6 months
- Counseling on adherence and risk reduction
HIV post-exposure prophylaxis 
- Timing: Initiate as soon as possible (ideally within one to two hours after exposure)
- Drugs: A three-drug regimen is recommended (similar to cART treatment). Typically, this includes a nucleoside/nucleotide combination NRTI plus an integrase inhibitor:
- Measures after needle stick injury or other contamination
Special patient groups
HIV in pregnancy
Antepartum and intrapartum management
- Combined antiretroviral therapy (cART) is recommended throughout pregnancy and delivery.
- The mode of delivery and the use of additional IV zidovudine depend on the maternal viral load during the intrapartum period; both of which must be considered to reduce the risk of transmission of HIV to the infant.
- Zidovudine is also one of the few antiretroviral medications approved for HIV post-exposure prophylaxis in neonates.
|Intrapartum management of HIV|
|Maternal viral load near time of delivery||Delivery method||Intrapartum antiretroviral treatment||Infant prophylaxis|
|> 1000 copies/mL OR unknown viral load OR poor adherence to ARV treatment|
|50–1000 copies/mL|| || |
|≤ 50 copies/mL|| || |
- Postpartum management
- Diagnosis in infants: if < 18 months, diagnosis is confirmed via PCR, not ELISA