Elizabeth A. Cahill
Abstract. Figures from 2004 suggest that as many as 42.3 million people, 1.1 percent of the world’s population, are currently infected with the human immunodeficiency virus (HIV). In Sub-Saharan Africa, the region suffering most from this pandemic, it is estimated that one in four adults will be killed by acquired immune deficiency syndrome (AIDS) (deWaal, 2004). HIV is a Lentivirus that infects T-helper cells, macrophages and monocytes. The host immune system reacts by removing its own infected T-cells, making the patient more susceptible to opportunistic infection. Chemotherapeutic drugs may drastically reduce morbidity and mortality of patients. These are available to less than 2% of persons with advanced AIDS. Despite much research into various types of vaccines, an effective vaccine against HIV has yet to be developed.
http://bahankuliahkesehatan.blogspot.com/
15 September 2004
Research sponsored by DARPA Grant DAAD19-02-1-0288, P00001
1 September 2004
Reed College, Portland, OR
DARPA Grant
Introduction
Just under twenty five years have passed since the Human Immunodeficiency Virus (HIV) was first described (Barre-Sinoussi et al., 1983) and already twenty million people have died (UNAIDS global report, 2004), approximately 14 times the population of the island of Manhattan (US Census data 2000). Despite the enormous amount of research that has gone into vaccine and therapy development, no cure has been found and the number of people with HIV continues to grow. At the close of the year 2003, UNAIDS estimated that 42.3 million people were currently infected. Of the twenty million people dead, approximately 2.9 million died last year alone (Steinbrook, 2004). This pandemic is changing the face of the world.
The enormity of these numbers makes them difficult to comprehend. Some more staggering numbers help to make this figure more accessible. Among adults aged 15-49, 1.1 percent are currently infected (Steinbrook, 2004). Each day approximately 14,000 new infections are established; 95% of new infections occur in developing countries (Emini and Koff, 2001). Every country in southern Africa reports HIV infection rates ranging from 20%-35% (deWaal, 2004). In sub-Saharan Africa approximately 1/3 of children (under age 15) have lost one or both of their parents. In some countries in Africa, there are more than one million orphans (Lewis, 2004). Reversing these trends will be an enormous struggle but is tremendously important. The implications of these numbers and the social challenges surrounding this epidemic cannot be discussed in this paper. However, it is important to consider the macroscopic reality of the HIV crisis when considering the virology of the disease. This virus has created a crisis that demands a global effort. For scientists, politicians and individual citizens it must simultaneously be treated as a pressing crisis and a long-term reality. Both types of strategies are essential.
Basic virology
Human Immunodeficiency Virus (HIV) is an infection of the immune system. Other immune system infections include Lupus, asthma and Crohn’s disease. To date, no human has been able to overcome an infection with HIV, although some persons have been able to force viral loads to below the level of detection. The most common modes of HIV infection are direct blood exchange (intravenous drug use or blood transfusion), sexual contact and mother to child transmission. Each of these infection routes can be dampened with appropriate protection strategies.
An understanding of the basic virology of HIV is necessary for discussions of vaccine and chemotherapeutic developments and challenges. HIV is a retrovirus. This indicates that it is an enveloped RNA virus that uses the enzyme reverse transcriptase (RT) to convert its viral RNA into a complementary DNA (cDNA). The resultant cDNA, during a successful infection, is inserted into the host chromosomal DNA where it is able to utilize host machinery, and energy, to further replication and infection. One important feature of RT is that it is error-prone. This serves to increase the virus’ genetic variability and the rate of variant evolution. Retroviral infection can cause numerous diseases, malignancies and cancer. HIV belongs to the genus Lentivirus (“slow virus”), a subset of the family Retroviridae. Lentiviruses are generally larger than other retroviruses and, as their name suggests, have long incubation periods. Every lentivirus causes immune deficiencies and nervous system dysfunctions (Flint et al., 2000) and can be responsible for malignancies such as arthritis or autoimmune disorders.
For an infection to be established the virus must adsorb to the host cell surface. Therefore, the availability of surface receptors determines the host and tissue specificity of any viral infection. In HIV the major viral receptor is a cell surface CD4 protein found on T-helper cells, macrophages and monocytes (Prescott et al., 2001). The humoral and cellular host immune systems both respond to the new infection. The humoral immune system is responsible for the production of antibodies again HIV-1. Antibodies bind to the virus, targeting them for destruction. The cellular immune response is activation of cytotoxic T lymphocytes (CTLs) that directly remove cells presenting viral antigens. The combined efforts of these two limbs of the immune system are insufficient to clear the virus. The continued viral replication in the cells of the lymph nodes ultimately leads to the destruction of the host lymph node structure (Prescott et al., 2001).
The fact that the virus targets both regulatory and antigen presenting immune system cells partially explains the virus’ total ability to avoid destruction by the host immune system (Emini and Koff, 2004). A coreceptor is necessary for viral fusion to the host membrane; it is the binding ability of the coreceptor that determines the tropism of the HIV strain (Flint et al., 2000). During the initial stages of HIV infection the corecptor to the moncyte or macrophage CD4 (M-tropic), CCR5, is essential. Persons homozygous for a mutated, and therefore nonfunctional, CCR5 receptor are impervious to HIV infection (Sullivan et al., 2001). Those heterozygous for the CCR5 receptor maintain a lower viral load during the pre-AIDS course of the disease and appear to progress to AIDS more slowly (Prescott et al., 2001). Mutations in the CCR5 receptor are extremely rare in many regions, such as sub-Saharan Africa and Asia, a fact that may alter the face of HIV/AIDS epidemiology in those regions (Sullivan et al., 2001). After the virus has been established in the host system, the T-cell tropic fusin (CXCR-4) protein is the coreceptor that determines the success of the virus (Prescott et al., 2001). Fusion facilitates the formation of syncitia. This is not seen in M-tropic strains.
All retroviruses have three common structural proteins Gag, Pol, and Env, which code for the core proteins and structural components of the virion, the reverse transcriptase and the envelope glycoprotein, respectively (Flint et al., 2004). Once the HIV-1 virus gains access to the host system, the viral gp120 Env protein binds the CD4 plasma membrane receptor on a host T lymphocyte. The gp120 protein is inaccessible to the host antibodies when it is unattached. It is able to bind CD4 only after a structural adjustment that exposes part of the gp120 to a chemokine receptor, such as CCR5 (Emini and Koff, 2004). The exposed part of the gp120 remains protected from antibodies by either steric hinderance or extensive glycosylation (Emini and Koff, 2004). Every fusion event is followed by the release of the virion core and RNA strands into the cytoplasm of the host T lymphocyte cell. The viral RNA is translated by viral RT into a single-stranded DNA (ssDNA). The RNA strand is then degraded; the ssDNA is used as a template to create a double-stranded DNA (dsDNA). At this point the virus either becomes latent in the cell or forces the cell to transcribe viral mRNAs. The formation of new virions within a host cell will ultimately destroy it, facilitating the release of thousands of new virions into the host system.
Because infected T cells are removed by the host’s own immune response, the patient’s immune response is necessarily compromised. As the loss of T cells becomes more advanced, the infected person becomes increasingly vulnerable to opportunistic infections because their immune system is less functional. These opportunistic infections are often the cause of patient mortality. The progression of HIV infection may be more aggressive in developing countries such as those in sub-Saharan Africa because of chronic infections with pathogens and parasites. Growing antibiotic resistance compounds this problem, making the treatment of other infections more challenging. However, the success of CTLs in removing the infected cells is not wholly destructive. The ability of the patient to clear infected cells, and therefore set the level of viremia during the asymptomatic phase, is a determinant of long-term HIV control. Therefore, the CTLs exert a strong selective pressure, which drives the formation of viral escape mutations (Leslie et al., 2004). HIV is also believed to carry oncogenes; cancer is another common demise of HIV patients. The central nervous system (CNS) can also be damaged because the virus is small enough to cross the blood-brain barrier.
There are roughly four stages described for the average course of an HIV infection. During the primary stage of infection the body produces an acute response to the introduction of the virus. Clinically, this period is best described by a general malaise but HIV antibodies can be detected in the body at this point and the patient is now infectious for the remainder of their lives. Normally, the host system manages to gain control over viral replication at this point and the viremia falls. The virus is not cleared but evades the host immune response and establishes a persistent infection (Emini and Koff, 2004). The patient is often asymptomatic during this phase, which lasts for a variable amount of time. Only approximately 10% of HIV positive adults exhibit disease progression in the first two or three years of infection. After ten years, 80% of HIV positive adults have signs of disease progression (Ho, 1997). During this period of clinical latency, destruction of the lymphoid tissues continues as the virus replicates (Fauci, 2003). The length of the asymptomatic phase poses an enormous challenge for disease control and epidemic modeling (Anderson and May, 1990). Eventually, the virus does overcome the host immune system and the symptoms of HIV/AIDS begin to emerge, the number of host T-cells drops and the patient historically will progress to AIDS at this point (T-cell count below 200 units). No survivors of AIDS have yet been recorded. The symptoms of AIDS are variable but can often include: fever, weight loss, skin rashes, diarrhea, dementia, myelopathy, peripheral neuropathy and increased susceptibility to any opportunistic pathogen (Fauci, 2003). More rare symptoms include Kaposi sarcoma, oral hairy leukoplakia and lymphomas (Flint et al., 2004).
Chemotherapeutic drugs have changed the quality and quantity of life that can be expected for HIV-positive persons who can afford to take them. The three general types of palliative drugs are RT inhibitors that are nucleoside analogs, nonnucleoside inhibitors of RT, fusion inhibitors and protease inhibitors (Prescott et al., 2002). The first effective treatment used to combat HIV was azidovudine (AZT), which is a RT inhibitor (McCleod and Hammer, 1992). A combination of these three types of drugs is most effective and results in greatly reduced morbidity and mortality in countries where they are available (Fauci, 2003). However, the virus does remain latent in T-helper cells and treatment must be continued indefinitely to avoid activation of the virus.
Vaccine development
In addition to the continued arms race for improved chemotherapeutic agents, a vaccine will be a necessary step towards slowing down the spread of this virus. Despite great efforts an effective vaccine remains elusive. Vaccines have historically been most effective in blocking diseases that have a period of acute illness such as smallpox, polio or tetanus. The fact that the host immune response has never been effective in clearing this virus indicates the challenge that biologists face in vaccine development. However, with approximately 14,000 new infections each day (Emini and Koff, 2004) it is a task of enormous importance.
An effective vaccine will have to induce, upon introduction of the virus, an immune response that is different, not just stronger or faster, than the naïve immune response. An obvious target in vaccine development is the Env surface protein, which is integral in establishing HIV infection, as discussed above. A vaccine based on the humoral arm of the immune system would produce antibodies to block new infections. A trimeric Env complex, which includes gp120 and gp41, triggers fusion when complexed with the CD4 receptor and an appropriate coreceptor. Neutralizing monoclonal antibodies (mAbs) have been developed for gp120 that interfere with binding to the CD4 receptor. Similarly mAbs designed for gp41 seem to block fusion. Neutralizing antibodies have been developed for many distinct regions in these glycoproteins but have not been effective in vivo (Burton et al., 2004). Gp120 quickly adapts to immune pressure forming variable surface proteins and gp41, although considered to be more stable, is kinetically inaccessible (Burton et al., 2004). Fortunately, there is a simian immunodeficiency virus (SIV) that is almost identical to HIV. Unfortunately, an effective vaccine has not yet been developed to withstand an SIV challenge (Desrosiers, R.C. 2004).
Another notable obstacle in the vaccine development effort is the sequence variability of the HIV-1 viruses to which humans are exposed. Goulder and Walker (2002) described cases where patients already infected with one strain of HIV-1 became infected again when exposed to a different strain. This has serious consequences for treatment as well as vaccination. In cases of superinfection, the same drug regime that is effective for one strain may not be effective for the other. The antiretroviral drugs used for treating HIV have severe side effects for many patients and increasing the drug dosage or number of drugs may not be possible. A fully effective vaccine would have to protect against many different strains of HIV.
A vaccine designed for a cellular immune response would create anti-HIV-1 CD4+ memory and CD8+ CTLs (Emini and Koff, 2004). The humoral response would, theoretically, be more important to block the establishment of an infection. However, a stronger, faster cellular immune response could help to establish a lower viral load. This is important both for the morbidity of individuals and epidemiologically (Emini and Koff, 2004). This should not be undervalued. The fact that teenagers in every country in sub-Saharan Africa have a 50% chance of being infected with HIV (deWaal, 2002) makes it important to use realistic triage tactics in addition to seeking out a totally effective vaccine.
Microbicides are another strategy being pursued. An entirely effective microbicide (non-toxic, contraceptive or non-contraceptive, fully effective) is many years away (Lewis, 2003). Yet even a partially effective microbicide could save millions of lives. Vaccine and microbicide development can be seen as an important strategy for protecting women (Lewis, 2003). In many cultures women have neither the ability to protect themselves from exposure to this virus nor the power to handle the consequences of the illness. Both a vaccine and a microbicide could give a woman the ability to protect herself without the necessary consent of her partner.
Conclusions
This epidemic is unlike any the human race has encountered before and must be handled as such. In 1981, during the conservative years under President Reagan, when doctors in New York and California began to note this remarkable and horrible illness in young, gay men, the reaction was slow (Shilts, R., 1987). Public fear and indifference to the gay community made the work of the doctors dedicated to uncovering the root of this disease a battle (Shilts, R., 1987). Similarly, in September 2001, President Mbeki of South Africa questioned the link between HIV and AIDS and decided that zidovudine was too toxic to distribute in clinics. This ignored substantial research demonstrating that zidovudine could dramatically reduce the mother to child transmission of HIV (Lallemant et al., 2004). This trend of insistent ignorance and cruelty is seen repeatedly. In Russia, a group of medical school graduates wrote, in 1997, "We are . . . categorically opposed to combating the `new disease' AIDS! We intend . . . to impede the search . . . to combat this `noble' epidemic. We are certain that . . . AIDS will destroy all drug addicts, homosexuals, and prostitutes. . . . Long live AIDS!" (Field, 2004). Despite all of this, there is great cause, and need, for optimism. The pandemic has reached such staggering levels that honest discussions and massive changes are beginning. Education programs, condom and needle distribution programs and health care programs are growing. The World Health Organization aims to have 3 million people in treatment by the year 2005. This is a step towards the ultimate goal of total access to antiretroviral medications. HIV introduces a nontraditional security threat in addition to the massive human tragedy. Countries with high incidence of HIV infection are experiencing severe economic crises along with enormous demographic changes. The effects of the epidemic in regions such as sub-Saharan Africa will be felt globally. There is a constant call for the change in the behavior of those in high-risk populations. For health considerations, this is valid. However, an equally substantial change in behavior is needed in the general population to make the necessary funding and support available.
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