Virology

HIV is a retrovirus that contains two single strands of RNA. The world pandemic is predominantly caused by HIV-1. HIV-2 infection originating in West Africa tends to progress to AIDS more slowly and is less infectious. To gain entry into a human cell, the viral outer membrane protein gp120 binds to the CD4 receptors that are present on T helper lymphocytes, macrophages, dendritic cells and microglia. Coreceptors, such as the chemokine C-C motif receptor 5 (CCR5), are also used to enhance viral entry. The enzyme reverse transcriptase carried within the virus particle enables the production of proviral DNA in infected cells. Once proviral DNA has been integrated into the host genome, viral peptides are transcribed. Specific viral protease enzymes cleave these before the daughter virus particles are assembled.

Diagnosis

HIV infection is diagnosed by detection of antibodies to gp120. During seroconversion, p24 antigen is detectable in the serum before antibodies are produced. Rapid tests using a fingerprick of blood or a buccal sample are increasingly being used for diagnosis, particularly in outreach settings.

The disease is monitored by measuring the level of CD4 lymphocytes in peripheral blood. A normal lymphocyte count lies above 500 cells/mm³. There is a 10% risk of AIDS developing within 1 year when the CD4 lymphocyte count drops to 200 cells/mm³. This is the level at which primary prophylaxis against Pneumocystis jirovecii pneumonia is recommended. Using PCR technology, it is also possible to measure the concentration of viral RNA in the plasma. A high level of more than 100 000 particles/ml predicts rapid disease progression.

Where there is access to effective antiretroviral therapy, treatment is now highly successful with a near-normal life expectancy predicted. Widespread testing with minimal pretest discussion is now advocated because failure to test and diagnose early increases the risk of late presentation with potentially irreversible complications.

Treatment

Two treatment strategies are used:

Antiretroviral drugs targeting reverse transcriptase or viral proteases were the first classes to be developed and are most widely used in initial treatment. Newer drugs, including fusion inhibitors, entry inhibitors and integrase inhibitors, target other stages of the viral lifecycle. The aim of therapy is to reduce the level of virus in the plasma to zero with a combination of antiretroviral agents. First-line regimens usually comprise two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) combined with a nonnucleoside reverse transcriptase inhibitor (NNRTI). Protease inhibitors are used instead of the NNRTI if there is resistance or another reason not to use an NNRTI.

If treatment is successful, the immune system partially recovers with a rise in the CD4 count and the risk of opportunistic infection is decreased. If total suppression of viral replication is not achieved, resistant strains of virus will inevitably arise within the treated person over the course of a few months. This is because reverse transcription is inherently inaccurate, leading to a high rate of mutation. With each cycle of replication of the virus, which takes 48 hours, single point mutations arise that will confer reduced sensitivity to antiviral agents.

Unfortunately, HIV infects long-lived memory cells from which the virus can rapidly reseed the body on cessation of therapy. Eradication, and thus cure, is unlikely even after several years of treatment.

If immunodeficiency has already occurred, treatment and prevention of opportunistic infections are needed. This may include co-trimoxazole to prevent Pneumocysis pneumonia and, in individuals with severely suppressed immunity and CD4 counts below 50 cells/mm³, azithromycin and valganciclovir to prevent disseminated Mycobacterium avium complex infection and cytomegalovirus infection, respectively. Regular administration of antifungal agents may be necessary to control oral and vaginal candidiasis.

The prognosis has improved dramatically for those with access to treatment. AIDS is now regarded as a treatable chronic disease with a near normal life expectancy. Increased morbidity and mortality from cancers other than the traditional AIDS-related ones and cardiovascular disease are starting to be recognised.

Of note, antiretroviral drugs, particularly some of the protease inhibitors, have many potential interactions with other drugs through effects on the cytochrome P450 enzymes. This includes an increase in the rate of breakdown of the synthetic estrogens present in oral contraceptive pills.

Transmission

In most developing countries, HIV is principally spread through vaginal intercourse, with approximately equal numbers of men and women being infected. In developed countries, the majority of infections have been acquired through homosexual sex or intravenous drug use, although the incidence of heterosexual transmission is increasing. Genital infections, including genital ulcer disease, chlamydia and gonorrhoea, are risk factors for HIV transmission and acquisition. Bacterial vaginosis may also be a risk factor and is very common in some African countries, with a prevalence of 50% or greater. Good control of sexually transmitted infections should reduce the incidence of HIV infection.