Bioinformatics Education Dissemination: Reaching Out, Connecting and Knitting-together

HIV Problem Space
Background

OUTLINE

Overview

Specific questions addressed in this section:

  • What is HIV?
  • Where did HIV come from?
  • How is HIV transmitted?
  • What is AIDS?
  • How does HIV cause AIDS?

The ALIVE Study

Glossary

 


Overview

HIV (Human Immunodeficiency Virus) is a virus that infects and kills crucial immune cells called CD4+ T cells in humans. A healthy, uninfected person has about 800-1200 of these cells per microliter of blood. Over the course of HIV infection, this number gradually declines, leading to ever weaker immune function. The rate of decline varies widely from person to person. As the immune system deteriorates, the infected person becomes vulnerable to a number of secondary infections and cancers that are much rarer in healthy individuals. An HIV-infected (HIV+) person who contracts one of these opportunistic infections, or whose CD4 count drops below 200 cells/mL, is diagnosed with AIDS (Acquired Immune Deficiency Syndrome).

Regimens of antiviral drugs can slow the immune system deterioriation in infected patients and extend the life expectancy of those who have developed AIDS. However, there is at present no cure and no vaccine.


Specific Questions

View an animation of the Retrovirus Life Cycle from W. H. Freeman and Co. and Sumanas, Inc.

What is HIV?
HIV belongs to a class of viruses called retroviruses. Retroviruses are RNA viruses that, once inside a host cell, use an enzyme called reverse transcriptase (contained inside the viral core) to convert their RNA into DNA. This DNA, called the provirus, then inserts itself into the host's own DNA. The viral sequence data in this problem space was isolated from proviral DNA.

Source: NIAID

A single HIV virus particle, or virion, is a sphere approximately 100 nn in diameter. The virus's outer coat, or envelope, is studded with copies of a protein called Env. This protein consists of two smaller glycoproteins: gp41 forms the stem and gp120 the tip. (These names derive from the number of amino acids in each glycoprotein.)

A great deal of study has focused on one part of the gp120 glycoprotein known as the V3 (variable region #3) loop. The V3 loop is involved in both the virus's infection of host cells and in recognition of HIV by the immune system. The sequence data in this problem space comes from a region of the env gene that codes for the V3 loop.

HIV Map Source: LANL

 

Detailed map of env gene:

 

detailed map of env gene Source: LANL

Where did HIV come from?
There are actually two genetically distinct types of HIV, HIV-1 and HIV-2. The two types are about 15-30% different at the DNA level. Both strains cause AIDS, although HIV-1 appears to be more virulent than HIV-2. There is some evidence that infection with HIV-2 may help protect against subsequent infection with the more virulent HIV-1. Epidemiologically, HIV-1 has spread around the world, while HIV-2 is mostly restricted to western Africa.

<maps>

Both types of HIV fall into a category of retroviruses known as lentiviruses, or slow viruses, so called because symptoms don't appear until long after initial infection. Similar lentiviruses are found in other species, causing immunodeficiency and slow wasting orders similar to AIDS in humans.

<lentivirus phylogeny>

Phylogenetic analysis comparing HIV to the various SIVs found in other primates reveals that HIV-1 is most closely related to SIVcpz (from chimpanzees), while HIV-2 is most closely related to SIVsm (from sooty mangabeys). This result suggests the two forms of HIV have distinct origins and represent separate epidemics. In fact, both HIV-1 and HIV-2 are thought to have been transmitted to humans from their simian host species on several distinct occasions, most likely through eating infected animals. Moreover, SIVcpz itself appears to be a recombination of two other SIV strains (Bailes et al. 2003).

How is HIV transmitted?
Despite the global nature of the AIDS epidemic, HIV is actually a very fragile virus and quite difficult to transmit. It can survive only a few minutes outside the body. The most common ways that HIV is spread are:

  1. Unprotected sex. HIV is found in the semen, vaginal fluids, and blood of infected patients. As a result, anal, oral, and vaginal sex all carry some degree of risk unless a condom is properly used. The exact chance of transmission varies widely depending on several factors.
  2. Sharing injection equipment (not just needles). Injecting infected blood directly into your bloodstream obviously carries extreme risk. Note that this chance of transmission applies when injecting any substance, including steroids. Use of non-sterile tattoo and piercing implements may also carry a slight risk.
  3. From mother to child. Transmission can occur during pregnancy, while giving birth, or through breast-feeding. HIV+ women can reduce this risk by taking antiretroviral medications during pregnancy, giving birth by C-section, and using safe substitutes for breast milk when available.
  4. Blood transfusions. Before blood screening was introduced, a significant number of people contracted AIDS from infected blood and blood products. Many countries, including the U.S., now test all donated blood for HIV (among other diseases); in these countries, the risk on infection is now less than 1 in one million, according to the American Red Cross.

It is equally important to understand how HIV cannot be transmitted. Ways that HIV does not spread include:

  1. Sharing glasses or toothbrushes or by using a swimming pool, shower, or toilet seat.
  2. Kissing, coughing, or sneezing. Saliva contains only minuscule amounts of HIV; studies indicate that this amount isn't sufficient to transmit the virus.
  3. Mosquito or other insect bites. The virus doesn't reproduce inside insects, and insects (unlike needles) don't inject people with blood from the source of their last meal.

What is AIDS?
AIDS (Acquired Immune Deficiency Syndrome) is a condition that eventually develops in many people infected with HIV. AIDS is associated with a seriously compromised immune system (200 CD4 cells/mL) and/or development of opportunistic infections such as Pneumocystis carinii pneumonia (PCP), Kaposi's sarcoma (KS), Candida infection (thrush), cytomegalovirus (CMV), cryptosporidiosis, and toxoplasmosis.

<peak-plain-plateau image>

When HIV first infects a patient, that person's immune system does not recognize the virus. As a result, the virus is able to reproduce rapidly. Approximately 6-8 weeks after initial infection, many patients experience a short illness with flu-like symptoms due to the high levels of circulating virus. At this point, the immune system is still strong, so it is able to produce antibodies that neutralize enough of the virus that symptoms vanish. Once these antibodies against HIV have been produced, the patient will test positive for HIV infection and is said to have seroconverted.

Unfortunately, the virus is still present and still reproducing rapidly. The immune system, working frantically, manages to keep the virus at low levels, so the patient remains asymptomatic. This stage lasts an average of ten years, though in many patients the duration is much shorter or much longer. In the end, the virus overwhelms the immune system and the patient develops AIDS.

Antiretroviral drugs can prolong the asymptomatic stage of HIV infection, though many require a rigorous dosage schedule and have extremely unpleasant side effects. Additional medications can help treat many of the opportunistic infections associated with AIDS. However, there is still no vaccine and no cure.

How does HIV cause AIDS?
There is still significant debate about the details of how HIV eventually overwhelms the immune system. One possibility is suggested by the antigenic diversity threshold hypothesis (Nowak et al. 1991). This hypothesis suggests that HIV's rapid mutation rate allows the virus to churn out a constant stream of escape mutants. Each such mutant strain is sufficiently different from the other strains infecting that patient that the immune system doesn't immediately recognize them and must develop antibodies specific to the new mutants. As more and more escape mutant strains appear, the immune system has to keep increasing the number of strain-specific antibody classes at the same time that it's being systematically attacked by the virus. Eventually, the virus builds up enough diversity that the immune system simply can't keep up.

A second way in which HIV may defeat the immune system is that more pathogenic strains evolve within the infected patient (Cheng-Mayer et al. 1988). In particular, most newly infected patients have viral populations that preferentially infect monocytes (a class of white blood cell). Over the course of infection, the viral population shifts to strains that preferentially infect T-cells. Moreover, about half of infected patients eventually develop strains that are SI (syncytium-inducing), meaning that T-cells infected with these strains tend to fuse with uninfected T-cells. This process kills the uninfected cells, greatly accelerating the rate at which HIV destroys the immune system (Koot et al. 1993).

These are just two of the many hypotheses about how HIV can cause AIDS. It's important to note that many of the hypotheses are mututally compatible; in other words, both viral diversity and the evolution of SI strains may play a role.

 

The ALIVE Study

The data in this problem space comes from the ALIVE study (AIDS Linked to IntraVenous Experiences), an ongoing study funded by NIDA (the National Institute on Drug Abuse). In 1988, this study began tracking 3,000 injection drug users in the Baltimore area; 24% of these were HIV-positive when the study began. Participants came in at roughly 6-month intervals for paid clinic visits that included interviews, physical examinations, and blood collection. Referrals for medical conditions, prenatal care, and drug abuse treatment were also offered.

The data in this problem space comes from a sample of 15 patients from the ALIVE study. These 15 were chosen on the basis of the following criteria:

Glossary

escape mutant: a strain of HIV, generated by random mutation within a specific patient, that is not recognized by the patient's immune system.

lentivirus: a class of retroviruses, including HIV, that produce few if any symptoms until long after initial infection.

longitudinal study: a study that monitors a specific group of individuals over time.

monocyte: a mononuclear white blood cell that circulates in the blood and can ingest foreign materials. When monocytes leave the bloodstream for other tissues, they differentiate into macrophages.

NSI (non-syncytium-inducing): a strain of HIV that doesn't cause syncytia to form. NSI strains usually predominate until late in infection, at which point SI strains evolve in about 50% of patients.

opportunistic infection: a secondary illness common in AIDS patients with severly depleted immune systems.

provirus: viral DNA that has inserted itself into the host's genome.

retrovirus: an RNA virus that undergoes reverse transcription upon infecting a host cell.

reverse transcription: production of a DNA copy from an RNA template; the opposite of the usual transcription process.

seroconversion: the point at which an infected patient has enough antibodies to HIV that he or she will test positive to standard tests for HIV infection; usually occurs 6-8 weeks after initial infection.

SI (syncytium-inducing): a strain of HIV that causes syncytia to form. During later stages of infection in about 50% of patients, SI forms evolve from pre-existingNSI strains.

syncytium: a multinucleated mass of cytoplasm enclosed by a single membrane. Some (SI) strains of HIV can form syncytia by causing an infected T-cell to fuse with uninfected T-cells.

tropism: the tendency to infect primarily a specific class of cell. For example, a strain of HIV that infects mostly T cells is said to be T-cell-tropic.

virion: a single virus particle.

Copyright ©1988-2013     BioQUEST, Inc.     Madison, WI 53744   (608) 363-2012 All Rights Reserved.