Acquired immune deficiency syndrome.

1. Acquired immune deficiency syndrome.

2. HIV pandemic • the number of infected people around the world continues to grow at an alarming rate • Estimates from the World Health Organization are that • more than 25 million people have died from AIDS since the beginning of the epidemic • and that there are currently around 33.5 million people living with HIV infection • Most of these are living in sub-Saharan Africa, where approximately 5.2% of adults are infected • In some countries within this region, such as Swaziland and Botswana, around 25% of adults are infected • There are growing epidemics of HIV infection and AIDS in China and in India, where surveys in several states have shown a 1-2% prevalence of HIV infection in pregnant women • The incidence of HIV infection is rising faster in Eastern Europe and Central Asia than in the rest of the world • About one-third of those infected with HIV are aged between 15 and 24 years, and most are unaware that they carry the virus

3. The number of new infections in 2008 has decreased by 30% compared with the apparent peak of the epidemic in 1996 • Worldwide, in 2008 there were around 33.5 million individuals infected with HIV, including some 2.7 million new cases, and more than 2 million deaths from AIDS • Data are estimated numbers of adults and children living with HIV/AIDS at the end of 2008 (AIDS Epidemic Update, UNAIDS/ World Health Organization, 2009

4. HIV- introduction • The earliest documented case of HIV infection in humans was reported in a sample of serum from Kinshasa (Democratic Republic of Congo) in 1959 • Officially reported in 1981 • The disease is characterized by a susceptibility to infection with • opportunistic pathogens or • by the occurrence of an aggressive form of Kaposi's sarcoma or B-cell lymphoma • It is now clear that there are at least two types of HIV-HIV-1 and HIV-2- that are closely related • HIV-2 is endemic in West Africa and is now spreading in India • Most AIDS worldwide, however, is caused by the more virulent HIV-1 • Both viruses seem to have spread to humans from other primate species, and the best evidence from nucleotide sequence relationships suggests that HIV-1 has passed to humans on at least three independent occasions from the chimpanzee

5. Infection with HIV generally occurs after the transfer of body fluids from an infected person to an uninfected one • Rates of transmission from an infected mother to a child • range from as low as 11% to as high as 60% depending on the severity of the infection

6. The virus is carried mainly in infected cells that express • CD4, which acts as the receptor for the virus, along with a • co-receptor, usually the chemokine receptors CCR5 (CD4 T cells, monocytes, macrophages and DCS)or CXCR4 (activated T cells) • The gastrointestinal and genital mucosae are the dominant sites of primary infection • Free virus is also present in blood, semen, vaginal fluid, or mother's milk • HIV virions seem to establish infection initially in a small number of mucosal CD4 T cells, where they replicate locally before spreading to lymph nodes draining the mucosa • The lymphoid compartment of mucosal tissues is enriched for memory CD4 T cells that express CCR5 favoring viral replication • After accelerated replication in regional lymph nodes, the virus disseminates widely via the bloodstream, and in particular gains broad access to the gut -associated lymphoid tissues (GALT), where the highest number of CD4 T cells in the body reside Lentivirus, tropism

8. Course of HIV • The acute phase of HIV infection (viremia), influenza­ like illness (80% cases) • An adaptive immune response follows, which controls the acute illness and largely restores levels of CD4 T cells (CD4+ PBL) but does not eradicate the virus • The acute viremia is associated in virtually all patients with the activation of CD8 T cells, which kill HIV-infected cells, and subsequently with antibody production ,or seroconversion • in the peripheral blood and a marked decrease in the numbers of circulating CD4 T cells, the latter due largely to the extensive death of CD4 T cells in the GALT that are killed directly by viral cytopathic effects or indirectly by activation­ induced apoptosis • The cyto­ toxic T-cell response is thought to be important in controlling virus levels, which peak and then decline, as the CD4 T-cell counts rebound to around 800 cells f..L l-1 (the normal value is around 1200 cells f.ll-1). • By 3-4 months after infection, the symptoms of acute viremia have usually passed • The level of virus that persists in the blood plasma at this stage of infection, referred to as the viral set point, is usually the best indicator of future disease progression • There is then a period of apparent quiescence of the disease that is known as clinical latency or the asymptomatic phase This is the asymptomatic phase • Opportunistic infections and other symptoms become more frequent as the CD4 T-cell count falls, starting at about 500 cells lll-1. The disease then enters the symptomatic phase. • When CD4 T-cell counts fall below 200 cells lll-1, the patient is said to have AIDS • Note that CD4 T-cell counts are measured for clinical purposes in cells per microliter (cells lll-1), rather than cells per milliliter (cells ml-1)

9. CD4+ T cell killing • There are at least three dominant mechanisms that cause the loss of CD4 T cells in HIV infection • First, infected cells can be killed directly by the virus; • second, infected cells are more likely to undergo apoptosis; • and third, infected CD4 T cells are killed by CD8 cytotoxic lymphocytes that recognize viral pep­ tides. • In addition, regeneration of new T cells is also defective in infected people, suggesting infection and destruction of the progenitors of CD4 T cells within the thymus. • This deficiency in regeneration might provide an explana­ tion for the rapid progression of disease in infants.

10. Immune responses against HIV • Most people infected with HIV and remaining untreated go on to develop AIDS and ultimately die of opportunistic infections or cancer • A small percentage of people exposed to the virus seroconvert, making antibodies against many HIV proteins, but do not seem to have progressive disease, in that their CD4 T-cell counts and other measures of immune competence are maintained • These long-term non-progressorshave unusually low levels of circulating virus and are being studied intensively to discover how they are able to control their HIV infection • Another group consists of seronegative people who have been highly exposed to HIV yet remain disease-free and virus -negative. • Some of these people have specific cytotoxic lymphocytes and T Hl lymphocytes directed against infected cells, which confirms that they have been exposed to HIV or possibly to noninfectious HIV antigens • It is not clear whether this immune response accounts for clearing the infection, but it is of considerable interest for the development and design of vaccines

11. After a period of clonal homogeneity during the acute phase of infection, HIV begins to mutate rapidly as the antiviral CD8 T-cell response to infection progresses and selects for escape mutants that are no longer detected by the adaptive immune response. • This gives rise to many different variants in a single infection and to even broader variation within the population as a whole • Different variants infect different cell types, and their tropism is determined to a large degree by which chemokine receptor the virus uses as co-receptor • The variants of HIV that use CCRS infect dendritic cells, macro phages, and T cells in vivo, and are now usually designated as 'R5' viruses • 'X4' viruses preferentially infect CD4 • T cells and use CXCR4 (the receptor for chemokine CXCL12) as a co-receptor • Epithelial cells from the single-layer epithelium covering rectum and endocervix express CCRS and another HIV-binding molecule, glycosphingo­ lipid galactosylceramide, and have been shown to selectively translocate R5 • HIV variants, but not X4, through the epithelial monolayer • This allows HIV to bind to and infect submucosal CD4 T cells and dendritic cells. Infection of CD4 T cells via CCRS occurs early in the course of infection and continues, with activated CD4 T cells accounting for the major production of HIV throughout infection. Late in infection, in approximately 50% of cases, the viral phenotype switches to the X4 type that infects T cells via CXCR4 co -receptors, and this is followed by a rapid decline in CD4 T-cell count and progression to AIDS

12. A variety of opportunistic pathogens and cancers can kill AIDS patients. Infections are the major cause of death in AIDS, with respiratory infection with P. jirovecii and mycobacteria being the most prominent. Most of these pathogens require effective macrophage activation by CD4 T cells or effective cytotoxic T cells for host defense. Opportunistic pathogens are present in the normal environment but cause severe disease primarily in immunocompromised hosts, such as AIDS patients and cancer patients. AIDS patients are also susceptible to several rare cancers, such as Kaposi's sarcoma (associated with human herpesvirus 8 (HHV8)) and various lymphomas, suggesting that immune surveillance of the causative herpesviruses by T cells can normally prevent such tumors (see Chapter 16)

13. Mouse models • Knock in mouse models and Knock out mouse models • Transgenic mouse models • Constitutive • conditional • Disease animal models • Spontaneous mouse models • Chemically induced mouse models