Retroviruses

GENERAL CONCEPTS:

The Retroviruses are composed of three subfamilies, two that infect humans. They are:
- Oncornaviruses: HTLV 1, HTLV 2, HTLV 5
- Lentiviruses: HIV 1, HIV 2
The HTLV or Human T Cell Lymphotrophic Viruses are divided into three types based on the type of diseases they produce:
- HTLV-I produces cutaneous T-cell lymphomas,
- HTLV-II produces hairy T-cell leukemias,
- HTLV-V produces T-cell lymphomas and leukemias.
The HIV or Human Immunodeficiency Viruses are divided into two types based on the type of diseases they produce:
- HIV-1 produces Acquired Immunodeficiency Syndrome (AIDS),
- HIV-2 produces a related disease syndrome, restricted to W. Africa.
The Retroviruses are RNA viruses and their name is derived from the viral enzyme Reverse Transcriptase, which makes circular DNA from linear RNA. The viral DNA has the capacity to integrate into the host cell genome.
In general, the viruses are not cytopathic. The Oncornaviruses generally transform cells, causing leukemias, sarcomas and carcinomas. The Lentiviruses attack T-cells, all but abolishing the host immune response.

DISTINCTIVE PROPERTIES:

Most of the information about Retroviruses comes from studies of HIV.
HIV is enveloped and displays a viral glycoprotein (gp120) that recognizes and binds to the CD4 receptor on T-helper cells. This glycoprotein is antigenically variable.
The viral genome is composed of 2 positive strands of RNA that are 5'-capped and 3'-polyadenylated. A cellularly derived tRNA binds the 3'-end and serves as a primer for DNA synthesis.
The order of the genes encoded by the viral RNA is as follows:

These genes correspond to the following viral products or functions:
- LTR: The Long Terminal Repeats are used for integration of the virus into the host genome and also contain promoter and enhancer sequences.
- gag: The Group-specific Antigen corresponds to the core and capsid proteins.
- pol: This gene encodes the reverse transcriptase, which actually has several functions.
- env: This Envelope gene encodes the gp120 glycoprotein.
- tax/rex: This region encodes factors involved in transactivation and other regulatory functions.
Upon entering a host cell, translation of the RNA produces a polyprotein that is cleaved to give the individual components. Cleavage of the polyprotein requires a specific protease that is the target for new anti-HIV drugs.
During replication, the reverse transcriptase (RT) uses the tRNA as a primer for DNA synthesis, creating a DNA/RNA hybrid duplex. Next, RT degrades the RNA strand using its RNAseH function and synthesizes a new DNA strand to produce a DNA duplex that circularizes. The circular DNA then integrates into the host genome, where it remains to be transcribed to produce new progeny RNA molecules. Following replication, the viruses escape by budding.

PATHOGENESIS:

HIV is transmitted via body fluids. Blood is the best and persons can acquire through sex, parenteral drug usage or transfusions.
The virus has a specific trophism for CD4⁺ (T-helper) cells. Following infection, it may remain latent for many years. Eventually, the infected T-cells lose their ability to function, resulting in a loss of both humoral and cell-mediated immunity.
Patients generally die of secondary manifestations including Kaposi's sarcoma or opportunistic infections.
Several specific syndromes are associated with infection by HIV. These include:
1. Lymphadenopathy and fever has an insidious onset and is characterized by weight loss and malaise.
2. Opportunistic infections: Many diseases that rarely affect normal individuals may occur in persons infected with HIV. These include: Pneumocystis carinii pneumonia, Candidiasis, severe Herpesvirus infections and frequent diarrhea caused by Salmonella, Shigella and Campylobacter.
3. Malignancies: Kaposi's sarcoma is a rare type of cancer that occurs in HIV-infected persons. These normally benign lesions become malignant and disseminate to involve visceral organs.
4. Wasting: Also known as "slim disease", this syndrome is common in Africa.
5. AIDS dementia: This condition mimics Alzheimer's disease and may involve HIV infection of the brain.

EPIDEMIOLOGY:

The first case of AIDS was described on June 5, 1981. Now, there are estimated to be more than 30 million total HIV infections worldwide. About half of these are in sub-Saharan Africa and about one-tenth of them occurred in 1996 alone, giving daily infection rates of about 8500 per day, approximately 1000 in children.
Current global trends include the following:
- The majority of new adult HIV infections involves persons 15-24 years old,
- Between 75% and 85% of HIV-positive adults have been infected through unprotected sexual intercourse, with heterosexual (male-female) intercourse accounting for more than 70% and male-to-male intercourse accounting for approximately 5-10%,
- Transfusion of HIV-infected blood and the sharing of HIV-infected injection equipment by drug users account for 3-5% and 5-10% of all global adult infections, respectively.
In the US, approximately 750,000 persons are infected with HIV and about 580,000 have AIDS. The following graphic illustrates the distribution of AIDS throughout the US.
While the focus on HIV/AIDS has always been homosexual men, a much larger percentage of infections now occur in women and children. Men who have sex with men continue to provide about 40-50% of new HIV infections, while about 20% of new infections involve women and about 10% involve children. Many (92%) of these children are infected by vertical transmission (in utero or during birth).

In terms of race/ethnicity, overall AIDS infections in the US predominate in non-Hispanic whites, but the number of new cases in blacks has now exceeded those in whites. However, dividing the percent of cases by the percent of the population represented by each group reveals that a disproportionate number of cases occur in African-Americans and Hispanics. The following table illustrates these values:

Race or Ethnicity	# of AIDS Cases	% of AIDS Cases	% of Population	Cases/Population
Caucasian, not Hispanic	268,856	46.2	72.8	0.6
African American, not Hispanic	203,189	34.9	12.1	2.9
Hispanic	103,023	17.7	10.9	1.6
Asian/Pacific Islander	4,131	0.7	3.5	0.2
Native American/Alaskan Native	1,569	0.3	0.9	0.3
Race/Ethnicity not known	661	0.1	-	-

DIAGNOSIS:

Clinical: Diagnosis is often helped by the occurrence of rare diseases or infections such as Kaposi's sarcoma or Pneumocystis pneumonia or recurrent or serious opportunistic infections. The patient's history (life-style, drug use, etc.) is also informative.
Laboratory: Laboratory diagnosis is based on measuring HIV antibodies using the ELISA (Enzyme-Linked Immuno-Sorbent Assay) test. Positive results are confirmed with another test known as a Western Blot. Together, the two tests are more than 99.9% accurate.

CONTROL:

Sanitary: The use of condoms during sexual intercourse can greatly reduce the chance of infections. Some spermicidal creams may also have anti-HIV properties. Non-use of intravenous drugs or sharing of syringes/needles prevents direct inoculation or the virus into the blood. Testing of the blood supply reduces transmission by transfusion. Education is perhaps the best means of preventing disease.
Immunological: No vaccines are available but some possibilities do exist.
Chemotherapeutic: Anti-HIV drugs fall into three categories: the nucleosides, the non-nucleosides, and the protease inhibitors. Nucleosides and non-nucleosides are both known as reverse transcriptase inhibitors.
- Nucleoside reverse transcriptase inhibitors include: Retrovir (zidovudine, AZT), Videx (didanosine, ddI), Hivid (zalcitabine, ddC), Zerit (stavudine, d4T) and Epivir (lamivudine, 3TC).
- Non-nucleoside reverse transcriptase inhibitors include: Viramune (nevirapine) and Rescriptor (delavirdine).
- Protease Inhibitors include: Invirase (saquinavir), Norvir (ritonavir), Crixivan (indinavir) and Viracept (nelfinavir).
These drugs are often given in combinations of two or three in order to attack the HIV virus in different ways.