999+
Retroviruses belong to a family of enveloped RNA viruses (Retroviridae) that infect vertebrates. They are divided into five subgenera, with two members (Deltaretroviruses HTLV-1 and HTLV-2, and Lentiviruses HIV-1 and HIV-2) causing human disease. They can be exogenous, transmitted horizontally among hosts, or endogenous, inherited vertically through the genomes of their hosts. The virus requires a reverse transcriptase to convert the viral RNA genome into DNA, which integrates into host chromosomes and utilizes host proteins for gene expression and replication. Retroviruses can also be oncogenic through insertional activation of host genes. In humans, HIV is responsible for causing acquired immunodeficiency syndrome (AIDS), and HTLV-1 and HTLV-2 are the retroviruses that cause human T-cell leukemia/lymphomas.
Structurally, retroviruses are enveloped viruses with an RNA genome. The virion contains a highly error-prone RNA-dependent DNA polymerase (reverse transcriptase) that converts the viral RNA into DNA, which integrates into the host chromosome (Hu, 2012). They have a diploid genome, with two copies of RNA per viral particle. A lentiviral (HIV) genome is depicted below.
The life cycle of retroviruses can be divided into two phases: the early phase, which includes cell binding through integration of viral DNA into the cell genome, and the late phase, which includes expression of viral genes through the release of virions. Retroviral infection begins when the mature virion envelope glycoprotein interacts with co-receptors on the surface of a cell and fuses the membranes of the host cell and virion (Wilen, 2011). The viral reverse transcriptase (RT) then uses a host tRNA whose 3' end is complementary to the sequence near the 5' end of the viral RNA and acts as a binding site for DNA synthesis. The RT thereby creates an RNA-DNA duplex, which is a substrate for RNase H to remove the 5' end of the viral RNA, resulting in a newly synthesized minus-strand DNA that can then act, through a complex series of steps, as a template for synthesizing linear double-stranded DNA (reviewed by Hu, 2012). The double-stranded DNA is circularized and transported to the nucleus, where it integrates into the host genome, is transcribed back into viral RNA that is translated to produce viral proteins, and the capsids are then assembled into viral particles and budded from the cell (Nisole, 2004).
The Deltaretroviruses (HTLV-1 and HTLV-2) have a worldwide distribution and are commonly found in southwest Japan, the Caribbean, and West Africa, where the incidence rate can reach 30% of the population. The virus is spread through sexual intercourse, blood transfusions, and breast feeding. Infection is mostly asymptomatic; however, a subset of infected individuals can develop one of the following: T-cell leukemia/lymphoma, an aggressive tumor of CD4 cells that occurs in 5% of infected individuals; HTLV-1-associated myelopathy (tropical spastic paraparesis), a non-demyelinating disorder with weakness in the lower limbs; infective dermatitis; or uveitis.
The Lentiviruses (HIV-1 and HIV-2) are the causative agents of acquired immune deficiency syndrome (AIDS). AIDS is a disease that arose in 1980, and HIV-1 is highly homologous to the simian immunodeficiency viruses that infect African monkeys and have crossed the species barrier. HIV-2 is most homologous to an SIV strain that entered the human population in the 1940s. Both viruses are most commonly transmitted between humans through sexual intercourse, but can also be transmitted vertically in utero, at childbirth, or through breast feeding.
The clinical course of HIV begins with a self-limiting febrile infection 2-4 weeks after exposure, with symptoms of fever, lymphadenopathy, and diarrhea, during which time the host develops antibodies. This is followed by an asymptomatic phase that can last years, when the patient enters clinical latency; they are infectious but largely asymptomatic, and test positive for HIV antibodies.
The prodromal phase begins with a drop in the CD4+ count, when patients begin to experience weight loss, fever, lymphadenopathy, oral candidiasis, and diarrhea. The disease then progresses to AIDS, which is characterized by fever, diarrhea, weight loss, skin rashes, neuropathy, myelopathy, dementia, and increased susceptibility to opportunistic infections such as TB, HSV, oral candidiasis, cryptosporidiosis, and pneumocystis infections, as well as other viral and fungal infections and virally induced malignancies such as Kaposi's sarcoma, hairy leukoplakia, and lymphomas.
Disease pathogenesis begins when HIV infects dendritic antigen-processing cells (DCs) in the oral and genital mucosa, attaching via a DC-SIGN receptor on the cell surface. HIV particles are then transported to CD4+ helper T-cells, where many cycles of infection are established in lymphoid tissues. Loss of function and death of CD4+ helper T-cells results in a drop in the helper T-cell count. Clinical disease progression correlates with the loss of CD4+ cells and may take five to ten years to progress from primary infection to complete failure of the T-cell-mediated immune response.
Early diagnosis depends upon the detection of viral DNA or RNA by PCR, or the detection of p24 antigen in serum. The p24 antigen is usually cleared once patient antibodies appear, so this test is most useful during the early window period, which occurs six days before the development of antibodies and 3-5 weeks after initial exposure.
Treatment of HIV infection includes antiviral agents that disrupt the viral replication cycle. A regimen of three drugs (HAART) given simultaneously suppresses HIV replication, but these drugs are not cures; they must be taken for life to maintain viral suppression. They include nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors. Short courses of anti-retroviral drugs have also been effective in preventing HIV infection following exposure.
There is currently no effective vaccine for the prevention of HIV infection, largely due to: