Human Immunodeficiency Virus (HIV)

Categorization
Genome: RNA Virus, Retrovirus	Structure: Enveloped Virus, Icosahedral Virus

Overview

Human Immunodeficiency Virus (HIV) is the viral etiologic agent that causes Acquired Immunodeficiency Syndrome (AIDS). Here we discuss the relevant virology of HIV along with clinical aspects of infection with this virus; however, the syndrome of AIDS is discussed separately (See page). Review retroviruses for a general discussion of this class of viruses.

Transmission

Sexually Transmitted Disease: Can occur during both heterosexual and homosexual sexual contact
Mother-to-Child Transmission: Can occur through placenta, during delivery, or via ingestion of breast milk
Parenteral Transmission: Can occur through IV drug Use or blood transfusion although with extensive donor screening measures is not rare due to the latter

HIV Replicative Cycle

Here we discuss the relevant features of the HIV Replicative Cycle (Review: Viral Replication for a general introduction). Importantly, the HIV replicative cycle displays general features of all Retroviruses (see page).

HIV attaches to host cells using its Envelope Protein gp120 which has a high affinity for the CD4 T-cell Coreceptor expressed on CD4+ T-cells as well as macrophages and Dendritic Cells. For infection to occur, host cells must also express CCR5 which acts as a co-receptor for gp120 binding. Surprisingly, a small percent of individuals with European decent do not express CCR5 and consequently cannot be infected by the virus.

Binding of gp120 to host cell receptors causes a conformational change which induces fusion of the viral envelope with that of the host cell, allowing entry of the viral capsid into the host cytosol. Following uncoating, pre-packaged viral reverse transcriptase begins to reverse transcribe the viral ssRNA genome into a DNA copy which then integrates within the host genome through the action of pre-packaged viral integrase enzymes.

Fresh copies of the ssRNA viral genome are transcribed from the integrated DNA copy similar to transcription of any host gene. The transcribed genome is also translated into viral structural proteins. Importantly, viral structural proteins are translated first into one long polypeptide which is then cleaved through the action of virally-encoded protease.

Fresh HIV virions are assembled at the host cell surface and are released by shedding.

Clinical Natural History

The natural history of HIV infection can be sub-divided into a number of sections characterized by the initial infection followed by a variable but generally long period of clinical latency that ultimately ends with symptomatic disease due to severe attrition of cell-mediated immunity. In the absence of laboratory diagnosis, infection usually comes to light only at this final stage.

Initial infection with HIV is followed by an acute period of significant viral replication and dissemination throughout the body. In nearly half of infected individuals the HIV virema is so significant that substantial constitutional symptoms arise along with a generalized lymphadenopathy, mimicking an acute mononucleosis-like syndrome. The majority of replication occurs within CD4+ T-cells whose numbers drop significantly within blood. However, within 3 months the immune system is able to organize an effective cell-mediated immune response that brings the infection under control. This is possibly achieved through the development of antigen-specific CD8+ T-cells which kill infected cells. Although antigen-specific antibodies are developed, these do not appear to be effective. Over time, viremia drops to low levels and the number of CD4+ T-cells recover, although never fully.

A period of clinical latency develops following the initial infection which can last a variable amount of time but usually about a decade. Clinical latency displays little symptomology and is characterized by an ongoing balance between viral replication and the immune response which results in chronic, low-level viremia. Throughout the course of latency, the numbers of CD4+ T-cells in the blood progressively decline, eventually reaching such a low threshold that substantial defects in cell-mediated immunity arise, resulting in symptomatic disease.

The symptomology of HIV infection is ultimately not due to the direct pathological effects of the virus but rather marks the end point of a progressive attrition of cell-mediated immunity. The two basic types of diseases which cause symptomology are opportunistic microbial infections and neoplasms. These are described as part of Acquired Immunodeficiency Syndrome.

Diagnosis

Antigen-specific antibodies to HIV proteins are most commonly used for diagnosis of HIV and become positive within a month following infection. These include antibodies to the viral core protein p24 or the viral envelope protein gp120. However, anti-HIV antibodies may not be present early in the course of infection when the immune response has not fully matured or very late in the course of infection when the immune response is highly deranged. Consequently, direct detection of HIV molecules may be helpful in these scenarios.

Direct detection of virus can be made by PCR-based strategies which detect the viral genome or by detection of the viral core protein p24. These methods can be used to diangose the virus or monitor the effectivness of anti-retroviral therapy.

Treatment

HIV treatment strategies are usually tailored to the patient and take into account their current immune status and previous treatment history. In general, the basic goal is to treat patients with multiple pharmacological agents with different mechanisms of action to avoid development of resistant strains. Therefore, treatment usually involves combinations of different HIV Antiviral classes, including: HIV NRTIs, HIV NNRTIs, HIV Protease Inhibitors.

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