In the past 20 years we have learned that about 5% of individuals who are infected with HIV have a natural immunity against the virus, and may not develop AIDS for years. Scientists now understand the biological mechanism for this natural protection: a protein that is secreted by certain groups of white cells in these individuals. We stand at the threshold of finding the CAF protein because of years of careful studies by Dr. Levy and many other scientific contributors to the field.
Download a white paper describing innate immunity against HIV.
Innate immunity: the basics
Innate immunity describes the natural ability of individuals to stop an infection before it even starts. Innate immunity against HIV occurs within minutes to days after the body first detects a microbe. In the case of HIV, the immune system of some virus-infected individuals quickly locks down the virus naturally: HIV never replicates. These healthy infected people have strong innate immunity towards HIV and make a special anti-HIV protein(s) inside a subgroup of their white cells. These white cells are called CD8+ lymphocytes. These individuals are infected – HIV can be detected in their blood – but they remain healthy, often for decades, without developing AIDS. The naturally protective protein secreted by the CD8+ cells is called the CD8+ Cell Antiviral Factor: CAF.
Our goal is to find the immunologic secret that naturally protects the 5% of HIV-infected individuals who never develop AIDS.
Ours is a fundamentally different approach to treating HIV infection. All other forms of marketed anti-retroviral drugs eventually lose control of the virus because the virus mutates. Over time, these HIV-infected individuals develop AIDS. Moreover, anti-retroviral drugs have toxic long-term side effects.
With our approach, HIV should not replicate and should not escape pharmacological control. Individuals infected with HIV could avoid taking toxic anti-retroviral drugs. They could remain relatively healthy and economically productive. Our approach can stop HIV from growing within the infected individual, and prevent AIDS from ever developing.
In contrast to innate immunity, 'adaptive immunity' describes immune activity that develops days to weeks after an infection. Through a complex set of steps involving two subgroups of specialized white cells known as T cells and B cells, the body makes antibodies via B cells that attempt to neutralize the infection ("neutralizing antibodies") and T cells that attack the virus-infected cells (CD8+ cytotoxic lymphocytes or CTL).
Adaptive immunity is therefore the second line of defense that becomes particularly important if innate immunity is not sufficiently strong. We view blocking HIV at the first opportunity – by strengthening the innate immune response, by increasing production of CAF protein – as a viable therapeutic strategy.
Because HIV/AIDS is still a pandemic
We are moved to act because HIV/AIDS is still a pandemic, and because there is a real need for other treatments, especially those directed at boosting the immune system.
Since the first HIV/AIDS patients were diagnosed almost 30 years ago, more than 66 million people have been infected. About 33 million people now live with the infection worldwide. Over 23 million people have died (UN AIDS Reports 2008). As their citizens grow sicker, countries with high numbers of HIV-infected individuals lose the benefit of their ability to care for their families, and their economic productivity.
Two-thirds (67%) of the global total of HIV-infected children and adults live in sub-Saharan Africa. Three-quarters (75%) of all AIDS deaths in 2007 occurred there.
Although the HIV/AIDS pandemic is coming under control in the industrialized world, it is a different story in the developing world (UN AIDS Report 2008). In southern Africa, where two-thirds of the world's HIV infection is clustered, prevalence in the adult population has "stabilized" at 15%.
While the level of infection in some countries has leveled off, it continues to increase in China, Indonesia, Papua New Guinea, Vietnam, Bangladesh and Pakistan.
Anti-retroviral drugs can be helpful and work after HIV has triggered an infection. These drugs try to slow the onset of AIDS by inhibiting the ability of the HIV virus to replicate, for example, by preventing the virus from attaching to, or entering into, or replicating inside of CD4+ cells. Over time, the virus outwits anti-retroviral drugs by mutating and escaping the pharmacological control. Even individuals fortunate enough to receive drugs for their HIV infection can eventually develop AIDS.
When an individual infected with HIV is first treated with anti-retroviral drugs, this is called "first-line" therapy. After the virus mutates and escapes control of first-line drugs, HIV-infected individuals may be given another set of drugs, or "second-line therapy." In the developing world, there are generic (less costly) versions of first-line therapy. There are currently no generic versions of second-line therapy. Ten years from now, most of the current branded "first-line" drugs will go off-patent.
As patients fail first-line anti-retroviral therapy, the cost of second-line therapy is rising faster than the ability of countries to pay for treatment. Assuming funding to low-income countries remains relatively constant, this means that fewer individuals will receive treatment for HIV, even as new and better medications are approved in the developed world. In some countries the rate of new infections is outstripping efforts to prevent and treat HIV/AIDS.
- Southern Africa remains the worst area hit by the pandemic: 1,000 people die in South Africa every week. The prevalence of HIV in adults exceeded 15% in seven southern African countries (Botswana, Lesotho, Namibia, South Africa, Swaziland, Zambia, and Zimbabwe) (UN AIDS Report 2008).
- In the United States, over one million people are estimated to be infected, of which 25% may not know they have HIV. About 1-2 people are infected every 15 minutes. Over 500,000 US citizens have died of AIDS since it was first recognized in 1981. Here at home, African-Americans are disproportionately affected (Black AIDS Institute 2008).
The impact of HIV varies considerably according to country and region. Impact depends on a government's and society's commitment to prevention, identification of infected individuals, and making treatment available and affordable. As shown in Figure 3 below, countries with large populations such as China and India, several million people have been infected and many have developed AIDS. (Source: UN AIDS Report 2008)
For further reading, two review papers by Dr. Levy (Levy 2001; Levy 2003) are available on our website. Dr. Levy has also written a book, HIV and the Pathogenesis of AIDS (ASM Press), now in its third edition.
Glossary
Adaptive immunity:
Adaptive immunity is the immune response that occurs within days to weeks after infection and is very selective in its activity against an infectious organism. Among its participants are T-lymphocytes and B-lymphocytes that participate respectively in cell-to-cell activities against infections and cancer and in the production of antibodies which circulate, attach, and inactivate organisms or help in the destruction of infected cells or cancer cells.
AIDS:
Acquired immune deficiency syndrome. This disease entity caused by the human immunodeficiency virus (HIV), a retrovirus, involves destruction of many aspects of the immune system, particularly T-lymphocytes that play a role in helping the immune system respond to infections and cancer (i.e. CD4+ T-helper cells). The number of these CD4+ T helper cells is generally 600 to 1,200/microliter (ml) of blood. In AIDS the number drops to below 200 cells/ml. The diagnosis of AIDS is given to patients whose CD4+ cells drop below 200 cells/ml and/or have developed an opportunistic infection such as Pneumocystis jureveci pneumonia, disseminated tuberculosis, and brain infections, or cancers, particularly Kaposi's sarcoma and B-cell lymphomas.
Antiretroviral therapy (ART):
This treatment involves drugs that have been developed to attack the human immunodeficiency virus (HIV). Most of them act by inhibiting the ability of the virus to produce a DNA copy of itself via the enzyme reverse transcriptase, its ability to integrate into the chromosome of the cell via integrase, or the ability of HIV to produce viral proteins in the right conformation via the enzyme protease.
CAF:
The CD8+ cell antiviral factor that mediates CNAR. This is a small protein released at very low levels by CD8+ lymphocytes and acts best during cell:cell contact.
CNAR:
The CD8+ cell noncytotoxic antiviral response (CNAR) is an innate immune activity of CD8+T cells that suppresses HIV replication within the cell without killing the cell. The arrest occurs after virus integration and blocks virus production.
Genomics:
A field of science which involves analysis of cellular genes encoding cellular proteins at the chromosome or DNA level or the messenger RNA level. Various microarray techniques and DNA and RNA genetic procedures have been developed for these analyses.
Immunotherapy:
This field of science involves the use of drugs or cells to restore or enhance the immune response against infectious organisms. This therapy can include approaches to increase the natural or innate immune response or adaptive or acquired immune activities.
Innate immunity:
Innate immunity is the natural first line defense against invading microbial organisms that can give rise to disease. This immune response is activated within hours to days after infection and is made up of both cellular and soluble participants (cellular products) that elicit responses of the other major immune activity, the adaptive immune response. Part of innate immunity is the secretion of the anti-viral protein interferon, as well as other cellular factors, or cytokines (interleukin-2, chemokines), that help immune cells replicate or bring immune cells to areas of infection or inflammation.
Long-term survivors, also called long-term non-progressors:
These are individuals who are infected with HIV, but remain healthy for at least 10 years with normal white cell counts and low levels of HIV in their blood.
Monoclonal antibodies:
Soluble proteins that are made by B-cells to a particular portion of an infectious organism. These antibodies can be used for detection of the organism and its proteins or for detection of various products or cytokines from cells. One mechanism for this detection process is the ELISA technique.
Proteomics:
The field of science by which various procedures including column chromatography and, eventually, mass spectrometry identify a protein which is part of a cell or produced by a cell. Stable isotope labeling of amino acids in culture (SILAC) is a recent method to quantitate differences in protein production by various cells. These approaches are needed to detect very low abundance (VLA) proteins that may be present in fluids or cells at extremely low amounts.
Retrovirus:
A virus that has RNA as its genomic material, and the enzyme reverse transcriptase for converting the RNA into DNA. During its replicative cycle, the retrovirus can make a DNA copy of its RNA genome and integrate the genetic material into the chromosome of a cell. Subsequently, the infected cell becomes a reservoir for viral production. Because the retrovirus does not necessarily kill the cell that it infects, the control of the infection must involve killing the infected cell or suppressing its production of virus.
T-lymphocyte:
A white cell (the T cell) that has been programmed after passage through the thymus to recognize incoming infectious organisms and respond to them. Some, such as CD4+T cells, help to increase the cellular immune response. Thus, CD8+T cells attack infectious organisms by killing the infected cell (cytotoxic activity) or controlling the infected cell through suppression of the organisms within the infected cell (suppressing activity).
Virus:
A virus is an encapsulated piece of genetic material (RNA or DNA) that is unable to replicate without the help of a cell. It is therefore a parasite within the cell it infects and uses the metabolism of the cell to reproduce its progeny viruses.