Dr Ekitumi Robert Ofagbor, MBBS.
AIDS is a disease caused by the retrovirus human immunodeficiency virus (HIV) and characterized by profound immunosuppression that leads to opportunistic infections, secondary neoplasms, and neurologic manifestations. The magnitude of the modern plague is truly staggering. By the end of 2006, more than a million cases of AIDS had been reported in the United States, where AIDS is the second leading cause of death in men between ages 25 and 44 years, and the third leading cause of death in women in this age group. Though initially recognized in the United States, AIDS is a global problem. It has now been reported from more than 190 countries in the world, and the pool in Asia and Africa is large and expanding.1. Over 22.9 million people in sub-Saharan Africa are infected with HIV, representing nearly 70% of the total population of people living with HIV and AIDS (PLWHA).2. The enormous medical and social burden of the AIDS problem has led to an explosion of research aimed at understanding HIV and its remarkable ability to cripple host defenses. The cardinal feature of HIV infection is the depletion of T Helper-inducer lymphocytes-the result of HIV replication in this population of lymphocytes as well as of the death of uninfected T cells by indirect mechanisms. The T cells express the CD4 phenotypic marker on their surface. The CD4 molecule is the major receptor for HIV; it has a high affinity for the viral envelope. The HIV coreceptor on lymphocytes is the CXCR4 chemokine receptor.3. The helper T cells are by far the most numerous of the T cells, usually constituting more than three quarters of all of them. As their name implies, they help in the functions of the immune system, and they do so in many ways. In fact, they serve as the major regulator of virtually all immune functions, as shown in the figure below. They do this by forming a series of protein mediators called lymphokines , that act on other cells of the immune system as well as on bone marrow cells. Among the important lymphokines secreted by the helper T cells are the following: Interleukin-2, Interleukin-3, Interleukin-4, Interleukin-5, Interleukin-6, granulocyte-monocyte colony-stimulating factor and Interferon-ᵞ.4. Loss of CD4 T cells is mainly because of infection of the cells and the direct cytopathic effects of the replicating virus.5. Approximately 100 billion new viral particles are produced every day and 1 to 2 billion CD4+ T cells die each day.6. CD4+ T cells play a pivotal role in regulating both cellular and humoral immune responses. Therefore, loss of the “master regulator” has ripple effects on virtually every other component of the immune system.1.
Since the beginning of the epidemic, almost 70 million people have been infected with the HIV virus and about 35 million people have died of AIDS. Globally, 34.0 million [31.4–35.9 million] people were living with HIV at the end of 2011. An estimated 0.8% of adults aged 15-49 years worldwide are living with HIV, although the burden of the epidemic continues to vary considerably between countries and regions. Sub-Saharan Africa remains most severely affected, with nearly 1 in every 20 adults (4.9%) living with HIV and accounting for 69% of the people living with HIV worldwide.7. In Nigeria, the HIV prevalence rate among adults ages 15–49 is 0.9 percent. Nigeria has the second-largest number of people living with HIV. The HIV epidemic in Nigeria is complex and varies widely by region. In some states, the epidemic is more concentrated and driven by high-risk behaviors, while other states have more generalized epidemics that are sustained primarily by multiple sexual partnerships in the general population. Youth and young adults in Nigeria are particularly vulnerable to HIV, with young women at higher risk than young men. There are many risk factors that contribute to the spread of HIV, including prostitution, high-risk practices among itinerant workers, high prevalence of sexually transmitted infections (STI), clandestine high-risk heterosexual and homosexual practices, international trafficking of women, and irregular blood screening.8. In Nigeria, an estimated 3.6 percent of the population is living with HIV and AIDS;
1. Although HIV prevalence is much lower in Nigeria than in other African countries such as South Africa and Zambia, the size of Nigeria’s population (around 149 million) means that by the end of 2009, there were 3.3 million people living with HIV.
2. Approximately 220,000 people died from AIDS in Nigeria in 2009.
3. With AIDS claiming so many lives, Nigeria’s life expectancy has declined significantly. In 1991 the average life expectancy was 54 years for women and 53 years for men.
4. In 2009 these figures had fallen to 48 for women and 46 for men.9.
HIV is a retrovirus, a member of the lentivirus genus, and exhibits many of the physicochemical features typical of the family. The unique morphologic characteristic of HIV is a cylindrical nucleoid in the mature virion. The diagnostic bar-shaped nucleiod is visible in electron micrographs in those extracellular particles that happen to be sectioned at the appropriate angle. The RNA genome of lentivirus is more complex than that of transforming retriviruses.3.
The typical course of untreated HIV infection spans about a decade. Stages include the primary infection, dissemination of virus to lymphoid organs, clinical latency, elevated HIV expression, clinical disease, and death. The duration between primary infection and progression to clinical disease averages 10 years. In untreated cases, death usually occurs within 2 years after the onset of clinical symptoms.
Following primary infection, there is a 4 to 11 day period between mucosal infection and initial viremia; the viremia is detectable for about 8-12 weeks. Virus is widely disseminated throughout the body during this time, and the lymphoid organs become seeded. An acute mononucleosis-like syndrome develops in many patients (50-75%) 3-6 weeks after primary infection. There is a significant drop in numbers of circulating CD4 T cells at this time. An immune response to HIV occurs 1 week to 3 months after infection, plasma viraemia drops, and levels of CD4 cells rebound. However, the immune response is unable to clear the infection completely, and HIV-infected cells persist in the lymph nodes.
This period of clinical latency may last for as long as 10 years. During this time, there is a high level of ongoing viral replication. It is estimated that 10 billion HIV particles are produced and destroyed each day. The half-life of the virus in plasma is about 6 hours, and the virus life cycle (from the time of infection of a cell to the production of a new progeny that infect the next cell) averages 2.6 days. CD4 T lymphocytes, major targets responsible for virus production, appear to have similar high turnover rates. Once productively infected, the half-life of a CD4 lymphocyte is about 1.6 days. Because of this rapid viral proliferation and the inherent error rate of the HIV reverse transcriptase, it is estimated that every nucleotide of the HIV genome probably mutates on a daily basis.
Eventually, the patient would develop constitutional symptoms and clinically apparent disease, such as opportunistic infections or neoplasms. Higher levels of virus are readily detectable in the plasma during the advanced stages of infection. HIV found in patients with late stage disease is usually more virulent and cytopathic than the strains of virus found early in infection. Often, a shift from monocyte-tropic or macrophage-tropic (M-tropic) strains of HIV-1 to lymphocyte-tropic (T-tropic) variants accompanies progression to AIDS.3.
CURRENT MANAGEMENT MODALITIES FOR HIV/AIDS
The management of HIV/AIDS involves the use of Antiretroviral drugs, development of candidate vaccines, and monoclonal antibodies development;
1) The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs in an attempt to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple drugs that act on different viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patient’s total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death.10.
2) An HIV vaccine is a vaccine which would either protect individuals who do not have HIV from contracting that virus, or otherwise may have a therapeutic effect for persons who have or later contract HIV/AIDS. Currently, there is no effective HIV vaccine but many research projects managing clinical trials seek to create one. There is evidence that a vaccine may be possible.11.
3) Work with monoclonal antibodies (MAb) has shown or proven that the human body can defend itself against HIV, and certain individuals remain asymptomatic for decades after HIV infection. Potential candidates for antibodies and early stage results from clinical trials have been announced.11.
NEW PROPOSITION FOR MANAGEMENT
The Above figure is a simplified representation of the basic workings of acquired immunity.
The current attempts at management with the use of antiretrovirals and treatment of opportunistic infections has led to significant decline in mortality and morbidity of HIV/AIDS but does not lead to viral clearance or complete cure.
The fundamental defect that leads to all the systemic manifestations in HIV infected patients is the depletion of both the quantity and quality of Helper T cells (CD4 T cells especially) which as previously stated is the trigger and regulator of acquired immunity via the action of lymphokines which it produces. This impairment leads to a decline in the body’s response to antigens leading to opportunistic infections, the effect of cytotoxic T cells is also compromised significantly and hence their cytotoxic function on virus infected cells is suboptimal. There is also impairment of antibody production because the lymphokines from the Helper T cells are depleted in HIV infected patient.
The recognition of this fundamental aspect of the pathogenesis of this infection makes the commonsensical deduction that synthetic lymphokines would impact positively on HIV management and possibly viral clearance and cure. The lymphokines activate a redundant immune system by acting on cytotoxic T cells which have a capacity to effect viral clearance and eventual cure. The advantage of this approach is that it would also lead to a significant decline in opportunistic infections theoretically as the immune system would continue to function as expected and the patients would be immunocompetent.
It is my earnest hope that this simplistic approach of replacing the deficient macromolecules (lymphokines) with synthetic alternatives that would take over the function of activating and regulating the components of the immune system especially the cyyotoxic T cells and plasma cells would not only improve morbidity of HIV patients, but could possibly lead to eventual viral clearance especially with persistent and correct use of antiretrovirals.
1) Kumar V., Abbas A. K., Fausto N., Aster J. Robbins and Cotran Pathologic basis of disease. 8th edition. Saunders Elsevier; 2004.
2) WHO/UNAIDS/UNICEF. Global HIV/AIDS Response: Epidemic update and health sector progress towards universal access 2011. Geneva: WHO, 2011.
3) Butel J. S. Jawetz, Melnick and Adelberg Medical microbiology 25th edition. Mcgraw hill lange; 2004.
4) Guyton A., Hall J. textbook of medical physiology. 11th edition. Saunders Elsevier; 2006.
5) Hazenberg M. D. et al. T cell depletion in HIV-1 infection: how CD 4+ T cells go out of stock; Nat immunol 1: 285, 2000.
6) Simon V. Ho D. D. HIV-1 dynamics in vivo: implications for therapy. Nat. Rev microbial 1: 181, 2003.
8) www.wikipedia.org/wiki/HIV/AIDS_in _nigeria