Human Immunodeficiency Virus

Published on 06/06/2015 by admin

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Last modified 06/06/2015

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95 Human Immunodeficiency Virus

Worldwide, more than half a million children younger than 15 years of age are infected with HIV. Untreated HIV infection leads to a complex immunosuppressive state that increases the risk of serious morbidities and mortality. A few decades ago, the diagnosis of HIV was thought to be a death sentence. In contrast, children born with HIV today can have essentially normal childhoods. Keeping HIV-infected children healthy requires the long-term administration of highly active antiretroviral therapy (HAART). Effective antiretroviral therapy must be combined with a holistic approach that considers the functioning and quality of life of the child and family.

Pathogenesis

HIV is a lentivirus that infects humans chronically, progressively damaging the hosts’ immune systems. Two viral types have been characterized in humans: HIV type 1 (HIV-1) and HIV type 2 (HIV-2). Based on viral genetic sequences, HIV-1 isolates have been classified into three groups (M, N, and O). The majority of HIV-1 strains identified worldwide belong to group M. Group M (“main group”) is classified into a number of subtypes (also termed clades). The subtypes are designated by letters (A, B, C, D, F, G, H, J, and K).

HIV begins its life cycle after entry into the human body when it binds to CD4 receptors and one of two co-receptors (CCR5 or CXCR4) on CD4+ T-lymphocytes and other receptor-containing cells. Binding to appropriate receptors allows the virus to fuse with the host cell, releasing viral RNA and enzymes into the host cell. The genetic material of HIV is single-stranded RNA. The virus also contains three enzymes that are essential to its replication: reverse transcriptase, integrase, and protease. Reverse transcriptase converts the single-stranded RNA into double-stranded DNA. Reverse transcriptase is a “low-fidelity” enzyme, meaning it is prone to making errors. On average, it inserts the wrong base into the growing cDNA chain at least every 4000 bases, producing mutated viral quasispecies. Over time, each infected individual accumulates a number of quasispecies that become “archived” within the host genome. The existence of drug-resistant quasispecies also creates a therapeutic challenge.

After reverse transcription, the double-stranded DNA enters the host cell’s nucleus, where viral integrase facilitates its integration into the host DNA. The integrated HIV DNA is referred to as a provirus. The provirus can remain inactive for years. Activation of the cell induces transcription of proviral DNA into mRNA. The mRNA migrates into the cytoplasm, where viral proteins are produced by the host cell. The viral protease cleaves the large viral proteins into smaller pieces to create the infectious virus. Two viral RNA strands and the replication enzymes are then surrounded by a capsid of core proteins. The viral capsid acquires a glycopeptide-studded envelope during budding from the host cell. These HIV glycoproteins are necessary for the virus to bind to CD4 and co-receptors. The process of viral replication leads to death of the host cell.

As many as 10 billion HIV virions are produced daily in a single human host. Untreated people typically have 103 to 106 virions per milliliter of plasma. The concentration of virus in lymph nodes is usually two to three orders of magnitude higher than in plasma. The amount of virus in the plasma is measured using quantitative HIV RNA polymerase chain reaction (PCR) tests, also called “viral loads.” Antiretroviral treatment aims to halt HIV replication and get the viral load down to undetectable levels.

Diagnosis

Within 6 to 12 weeks of infection with HIV, people produce HIV-specific antibodies, detectable by commercially available assays. Adults and children older than 18 months of age are typically tested for HIV with antibody-based assays such as rapid HIV immunoassays (“rapid test” or enzyme immunoassay [EIA]) and enzyme-linked immunosorbent assay (ELISA). A positive rapid test or ELISA result is usually confirmed with a Western blot test. These antibody tests are positive in virtually all HIV-infected individuals after the first 3 months of infection. The period during which the person is HIV infected but does not have detectable antibodies is referred to as the window period. With the currently available antibody assays, antibodies to HIV are usually detectable by 4 to 6 weeks after infection.

Babies born to mothers with HIV are considered to be HIV exposed and need to undergo testing for HIV. HIV-exposed babies will have positive HIV antibody test results, even if the infants are not HIV infected. Maternal anti-HIV immunoglobulin G (IgG) antibodies cross the placenta and can be detected in babies born to mothers who carry the HIV antibodies. On average, maternal antibodies to HIV persist in the infants for the first 9 to 18 months of life. Therefore, virologic tests are used to confirm the presence of HIV infection in babies who are younger than 18 months of age. Most commonly, HIV DNA PCR or HIV RNA PCR is used for diagnosis during this time. Negative (DNA or RNA) PCR test results done at 1 month and 4 months of age can rule out HIV infection in perinatally HIV-exposed babies who are not breastfeeding. HIV viral culture and p24 antigen assays may also be done for diagnosis but are considered less sensitive and specific than RNA and DNA PCR tests. Early negative HIV virologic test results can be confirmed by obtaining a negative antibody-based test result around 18 months of age.

Table 95-1 summarizes the expected results of HIV diagnostic tests for HIV-exposed and -infected infants and adolescents. Children older than the age of 18 months would have the same test results as adolescents in the same infection or exposure category.

Clinical Manifestations of Hiv Infection

The process of HIV replication leads to depletion of CD4+ T lymphocytes. The degree of immunologic suppression is classified based on the number and percent of CD4+ T lymphocytes present in the bloodstream. In young children, the normal number of CD4+ T lymphocytes is much higher than in adults. Therefore, age-specific absolute CD4+ T lymphocyte count ranges should be used to determine the degree of immune suppression in children. CD4+ T lymphocyte percents change less with age and can be used instead of absolute counts to classify the degree of immune suppression in HIV-infected children (Table 95-2).

Along with depletion of CD4+ T lymphocytes, HIV infection leads to functional defects in existing CD4+ T-lymphocytes and defects in B-cell function. These combined immunosuppressive processes lead to a number of clinical manifestations. The most severe and common of these manifestations are outlined in Table 95-3. Opportunistic infections, cancers, hematologic aberrations, and other noninfectious manifestations are among the most severe AIDS-defining conditions.

Table 95-3 Selected Clinical Manifestations of HIV Infection

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Severe Manifestations Description
Pneumocystis jiroveci pneumonia Definitive diagnosis via microscopy of induced sputum or BAL
Multiple or recurrent serious bacterial infections Septicemia, pneumonia, meningitis, bone or joint infection, internal organ infections
Kaposi’s sarcoma