HIV and HIV (AIDS) Infection Overview

What is HIV?

The human immunodeficiency virus (HIV) is a member of the genus Lentivirus in the Retroviridae family, a large and diverse family of enveloped RNA viruses. Retroviruses are so called because their RNA genome is transcribed into linear double-stranded DNA by a characteristic enzyme known as reverse transcriptase (RT), a RNA-dependent DNA polymerase that reverses the classical flow of genetic information. The DNA subsequently enters the nucleus and integrates as a DNA provirus into the host cellular genome. The integrated retrovirus then is either transcriptionally active producing virions or remains in a silent or latent state. Lentiviruses consist of a diverse group of animal viruses with certain clinical and biological characteristics. The human counterpart, HIV, was discovered because of its association with the AIDS. This clinical condition is characterized by a marked reduction in the numbers of CD4þ T cells and a loss in immune function leading to the development of various opportunistic infections and cancer.

HIV Genetic Diversity

Globally circulating strains of HIV-1 exhibit an extraordinary degree of genetic diversity, which may influence aspects of their biology such as infectivity, transmissibility, and immunogenicity. This characteristic may be attributed to the infidelity of the viral RT with DNA, suggesting that mutations occur with the DNA template–DNA primer.This enzyme has been found to be highly error prone, resulting in about ten base pair changes in the HIV genome per replicative cycle. One of the early differences to be recognized among various HIV-1 isolates was the variation in sensitivity of the cloned, proviral genome to restriction enzyme digestion. In another approach, DNA heteroduplex analysis on an agarose gel has been used to detect HIV-1 quasispecies diversity when evaluating different genetic regions (see ‘Detection assays for HIV’). When the complete genetic sequence data for the initial HIV-1 isolates became available, HTLV-IIIB and LAV were found to be the same isolate whereas SF-2 (formerly called ARV-2) and other HIV-1 isolates were different. Molecular analyses of various HIV isolates reveal sequence variations over many parts of the viral genome, particularly in the envelope region. Currently, on the basis of fulllength viral genome sequencing, HIV-1 has been classified into three groups: M (main), O (outlier), and N (Non-M or -O). Eight HIV-2 groups have been identified. Group M viruses are by far the most widespread and responsible for more than 99% of infections worldwide. Group M viruses have been divided into nine distinct genetic subtypes or clades, designated A to D, F to H, J, and K; and differ among themselves in amino acid composition by at least 20% in the envelope region and 15% in the Gag region. The groups have more than 25% difference in the envelope and Gag regions. Recombinant viruses are part of the viral genetic diversity. They emerge frequently in human populations where multiple clades co circulate, sometimes becoming an epidemiologically important lineage called as circulating recombinant forms (CRFs). The CRFs are numbered sequentially with the clades involved in recombination or are designated cpx (for complex) if more than four subtypes are involved .The viruses originally identified as subtypes E (the predominant group of viruses involved in heterosexual transmission in Thailand) and I (initially found in Cyprus) are now considered inter-subtype recombinants or CRFs and have been termed CRF-01AE and CRF-04cpx, respectively. In Africa, an inter-subtype recombinant, CRF-02AG, is the dominant virus type. Clades A through D and the inter-subtype recombinants CRF-01AE and CRF-02AG account for more than 90% of current infections worldwide. Subtype B is dominant in Europe, North and South America, and Australia. Subtypes A, C, and CRF-02AG are responsible for about 75% of new infections occurring globally. Clade C is the most prevalent clade and may represent up to 50% of all HIV infections worldwide. It is found predominantly in South Africa, India, and China. Clade D is predominant in Central Africa. CRF-01AE is the most prevalent virus in Southeast Asia. Subtype F includes isolates from Brazil and Romania. Other sequence subtypes (G, H, and I) include viruses from Africa, Russia, and Taiwan. Subtype K, whose env C2-V5 sequence branched within group M but remained distinct from all known HIV-1 subtypes, has been reported from Cameroon. In addition to group M, other isolates initially found in Cameroon and in other African countries at a low frequency are considered outliers and belong to group O. The prototype virus of group N was isolated in Cameroon and appears to be closer to the chimpanzee SIV than either groups M or O of HIV-1. Eight distinct sequence groups of HIV-2 (A through H) have been identified. Group A in Senegal and Guinea Bissau and group B in the Ivory Coast are the most commonly identified groups. Groups C, D, E, and F came were identified from rural areas in Sierra Leone and Liberia. The HIV-2 viruses appear to be most related to the SIVsmm isolates from sooty mangabeys found in the same areas.

HIV Transmission

After an acute HIV infection, a flu-like illness occurs that can last for up to 3–4 weeks. Sometimes a macular skin rash is also seen (Table 2). Those infected people who do not show this acute retroviral syndrome (ARS) usually have a better prognosis. The transmission frequency of a virus like HIV is greatly influenced by the amount of infectious virus in a body fluid and the extent of contact with that body fluid. Epidemiological studies conducted during 1981–1982 first indicated that the major routes of transmission of AIDS were intimate sexual contact and contaminated blood. The syndrome was initially described in homosexual and bisexual men and intravenous drug users but its transmission through heterosexual activity was soon recognized. High-risk sexual behavior early in the epidemic caused the rapid increase in HIV transmission. Subsequent studies showed that transfusion recipients and hemophiliacs could contract the virus from blood or blood products, and infected mothers could transfer the causative agent to newborn infants. Surveillance and epidemiologic data throughout the world continue to support strongly three primary modes of transmission: sexual contact (heterosexual and homosexual); exposure to blood, largely through injecting drug use and transfusion; and perinatal transmission from infected mothers to their infants. These means of transmission can be greatly explained by the relative concentration of HIV in various body fluids. Blood has high levels of both infectious virus and virus-infected cells; however, the amount of infectious virus is less than the number of HIV-infected cells that could transfer virus to an individual. HIV-infected cells in genital fluids appear to be a major source of transmission by the sexual route. Sexually transmitted diseases further enhance the risk of virus transmission to either partner by increasing the presence of virus-infected cells. Saliva is not a major source of transmission as it contains HIV-inhibitory substances and only small amounts of infectious virus. Transmission of virus from mother to child can involve direct infection of the fetus in utero or exposure of the newborn to maternal blood and secretions during birth. The major factors affecting this transmission are the levels of infectious virus in the mother at the time of delivery; amniotic fluid; and uterine, placental, and fetal tissues. The number of virus-infected macrophage and T cells in mother’s colostrum and milk also determines this transmission. Effective preventive measures for sexual transmission include condoms. Female condoms, diaphragms, vaginalmicrobicides, or compounds that inhibit HIV adsorption and cell-to-cell contact need further evaluation. Most recently, male circumcision has been shown to decrease transmission in men by up to 60%. Treatment of ulcerative genital diseases that can enhance HIV transmission also reduces infection. Highly active antiretroviral therapy (HAART) is being evaluated for use in postexposure prophylaxis (PEP). Antiretroviral therapy can also greatly reduce the risk of mother–child transmission.

Characteristics of acute HIV infection

Clinical Symptoms

• Headache, retro-orbital pain
• Muscle aches and joint pains
• Low-grade or high-grade fever
• Swollen lymph nodes
• Nonpruritic macular erythematous rash
• Oral candidiasis
• Ulcerations of the esophagus, anal or vaginal canal
• Acute central nervous system disorders (e.g., encephalitis)
• Pneumonitis
• Diarrhea and other gastrointestinal complaints

Course

• Symptoms usually appear 1 to 4 weeks after acute infection
• Symptoms last from 1–3 weeks
• Lymphadenopathy, lethargy, and malaise can persist for many months
• Generally followed by an asymptomatic period of months to years

Laboratory findings

• First week: lymphopenia and thrombocytopenia
• Second week: lymphocyte number rises secondary to an increase in CD8þ cells; CD4þ/CD8þ cell ratio decreases
• Immune activation reflected by increased cytokine levels (e.g., IL-1_, TNF_, and IFN_)
• Third week: atypical lymphocytes appear in the blood (generally <30%)
• HIV antigenemia and viremia detected within 3–10 days
• Virus can be present in CSF and in seminal fluid within 7–14 days
• Anti-HIV antibodies usually first detected within 1–3 weeks after acute infection\
• Proinflammatory cytokines increased in blood (e.g., IL-15 and TNF-_)

Detection Assays for HIV

Various assays for the detection of HIV have been developed since the recognition of AIDS. The virus’ presence in cell culture can be determined by RT activity. Immunofluorescence assays, ELISAs, and the Western blot help to detect antibodies to HIV. All these tests are confirmatory assays for HIV infection. Other procedures like measurement of viral p24 antigen (directly and after acid dissociation) and of HIV RNA levels by reverse transcription-PCR have increased the sensitivity for detection of HIV in blood and other body fluids. Even though these procedures do not distinguish between infectious and noninfectious virions, they have been particularly useful in monitoring the effect of antiviral treatment in HIV-infected individuals. The development of flow cytometry in the 1970s greatly helped to study the effect of HIV on the immune system as it enabled clinical and research laboratories, via selective monoclonal antibodies, to determine the number of CD4þ and CD8þ cells in humans. While the CD4þ/CD8þ cell ratio is usually 2:1, it was very soon recognized that the ratio in infected individuals often was reduced to less than 1. The number of CD4þ T cells, usually in the range of 600–1200 cells ml_1, became reduced over time, particularly in progressors, to the low hundreds (e.g., <300 cells ml_1). These findings supported the observation that the CD4þ  lymphocyte was a major target for HIV replication and cell death.