HIV and AIDS Acquired Immunodeficiency Syndrome Disease caused by an infectious agent: a retrovirus

HIV and AIDS History of an infectious agent In Los Angeles 1967-1978: only two cases of Pneumocystis carinii pneumonia 1979 - 5 cases of Pneumocystis carinii pneumonia All Homosexual Dot-like intracystic bodies of Pneumocystis carinii in lung Cytologic preparation from a bronchoalveolar lavage – Giemsa stain

HIV and AIDS With dissemination to extrapulmonary sites, Pneumocystis carinii tends to produce foci with prominent calcification, as seen in the kidney

HIV and AIDS an infectious agent – Kaposi’s Sarcoma Early 1981: 5 cases of Kaposi’s sarcoma Hitherto: rare (immunocompromization) Elderly - Non-aggressive 1981 - 26 cases of Kaposi’s sarcoma Young Male San Francisco and New York

AIDS Definition AIDS is currently defined as the presence of one of 25 conditions indicative of severe immunosuppression OR HIV infection in an individual with a CD4+ cell count of <200 cells per cubic mm of blood AIDS is therefore the end point of an infection that is continuous, progressive and pathogenic With the prevalence of HIV in the developing world, HIV and its complications will be with us for generations

AIDS Statistics Approximately 44,000,000 people in the world are HIV-infected Approximately 14,000 new HIV infections occur daily around the world Over 90% of these are in developing countries 1000 are in children less than 15 years of age. Of adult infections, 48% are in women and 15% in individuals 15-25 years

Global summary of the AIDS epidemic Number of people living with HIV in 2008 Total 33.4 million [31.1 million–35.8 million] Adults 31.3 million [29.2 million–33.7 million] Women 15.7 million [14.2 million–17.2 million] Children under 15 years 2.1 million [1.2 million–2.9 million]

Global summary of the AIDS epidemic People newly infected with HIV in 2008 Total 2.7 million [2.4 million–3.0 million] Adults 2.3 million [2.0 million–2.5 million] Children under 15 years 430 000 [240 000–610 000]

Global summary of the AIDS epidemic AIDS-related deaths in 2008 Total 2.0 million [1.7 million–2.4 million] Adults 1.7 million [1.4 million–2.1 million] Children under 15 years 280 000 [150 000–410 000]

HIV and AIDS

AIDS Statistics Sub-Saharan Africa About 1 million new cases of AIDS per year 30 million people with HIV infection AIDS is responsible for a decrease in life expectancy and increase in child mortality. Child mortality rates in East Africa will double by 2010 and adult life expectancy has declined in that region Several countries in sub-Saharan Africa report infection rates of 20-25%, especially urban areas Zimbabwe: 33.7% of adult population infected In Zambia, 1 in 5 urban girls is HIV-positive by the age of 20

SUB-SAHARAN AFRICA Number of people living with HIV 2008: 22.4 million 2001: 19.7 Number of new HIV infections 2008: 1.9 million 2001: 2.3 million Number of children newly infected 2008: 390 000 2001: 460 000 Number of AIDS-related deaths 2008: 1.4 million 2001: 1.4

Important Properties The virus only grows on T4 cells that are proliferating in response to an immune stimulus -- Therefore difficult to grow in culture Human immunodeficiency viral particles are seen at medium magnification in this electron micrograph (CDC)

TAT – REV – NEF – VIF – VPR – VPU HIV - The Virus Retrovirus Three genes GAG – POL – ENV Three polyproteins Six regulatory genes TAT – REV – NEF – VIF – VPR – VPU

HIV - The Virus Retrovirus ENV gene Two glycoproteins: gp160 gp120 and gp41 gp41 is fusogen that spans the membrane ENV gene

HIV - The Virus Retrovirus GAG gene Group-Specific Antigens p17: inner surface - myristoylated p24: nucleocapsid p9: nucleocapsid associated with RNA GAG gene Polyprotein

HIV - The Virus Retrovirus POL gene Enzymes Polymerase (reverse transcriptase – RNA dependent DNA polymerase) Integrase Protease (cuts polyproteins) POL gene Polyprotein

The Genome of HIV Three structural genes LTRs Extra open reading frames are clue to latency These ORFs code for small proteins - antibodies in AIDS patients

Viruses similar to HIV HIV-2: was isolated from AIDS patients in West Africa 1986 Simian immunodeficiency virus (SIV): was isolated from monkeys with an AIDS-like illness Human T-cell lymphotropic virus (HTLV-4): infect T cells, no kill, no disease

Summary of Replicative cycle Typical retrovirus cycle Entry: (gp120, binding ; gp41, fusion) - Chemokine receptors (CXCR4, CCR5) - Mutation in these receptors (infection??) Uncoating, Treanscription of viral RNA genome „RNA-dependent DNA polymerase“ Transcription of viral mRNA from proviral DNA by host cell RNA polymerase Translation to several large polyproteins Released by budding from the cell membrane

T4 (CD4+) cells are major target HIV - Life History Entry into the cell T4 (CD4+) cells are major target Human HeLa Cell transfected with CD4 antigen Human HeLa Cell Human HeLa cells are not infected by HIV because they do not have CD4 antigen. When CD4 gene was transfected into the HeLa cells, they became able to bind HIV and were infected. NOT INFECTED INFECTED

Chemokine receptors are necessary co-receptors along with CD4 antigen HIV - Life History HIV chemokine Mutant CCR5 CD4 CCR5 CD4 CCR5 CD4 macrophage Chemokine receptors are necessary co-receptors along with CD4 antigen

Transmission & Epidemiology Sexual contact Blood transfusion From infected mother to neonate or via breast feeding Infection occurs by transfer of either HIV-infected cells or free HIV 2/3 of AIDS victims living in Africa, Asia, & Latin america AIDS is the 4th leading cause of death worldwide

Pathogenesis & Immunity

The cellular and immunological picture - The course of the disease This time course of HIV infection applies to persons not receiving chemotherapy.

The cellular and immunological picture - The course of the disease

10 billion HIV particles per day Virus half life 5.7 hours 100-10 million virions per ml blood (set point) Small minority of T4 cells are infected Virus found in lymph nodes

Inexorable decline of CD4+ T4 cells Why do all of the T4 cells disappear? At early stages of infection only 1 in 10,000 cells is infected Late 1 in 40

Virus destroys the cell as a result of budding But few cells are infected: Early stage of infection 1:10,000 Late 1:40 Why do all T4 cells disappear? 1. PUNCTURED MEMBRANE

Why do all T4 cells disappear? But syncytia not common Most T4 cells are not HIV+ Could “sweep up” uninfected cells Infected CD4 cell Gp120 positive Cells Fuse Uninfected CD4 cell Gp120 negative Killing of CD4 cells 2. Syncytium Formation

Killing of CD4 cells 3. Cytotoxic T cell-mediated lysis Why do all T4 cells disappear? Cytotoxic T cell Killing of CD4 cells 3. Cytotoxic T cell-mediated lysis BUT: Most cells are not infected

Killing of CD4+ cells 4. Binding of free Gp120 to CD4 antigen makes uninfected T4 cell look like an infected cell Complement-mediated lysis Could account for the loss of uninfected T4 cells

Clinical Findings Erly, acute stage Middle, latent stage Late, immunodeficiency stage

Macrophages bring HIV into the body if sexually transmitted High virus titer Mild symptoms Fall in CD4+ cells but recovers Rise in CD8+ cells but recovers A high virus titer (up to 10 million viruses per ml blood) Macrophages infected Macrophages bring HIV into the body if sexually transmitted The cellular and immunological picture The course of the disease 1. Acute Infection HIV is now NOT replicating in resting T4 cells and most are resting in the peripheral circulation. At this time most replication is in lymph nodes in macrophages and dendritic cells. Symptoms are ‘flu or mononucleosis-like.There is a cellular immune response within weeks. Antiviral antibodies and cytotoxic T cells rise to high levels and persist for years. They are very effective at keeping the virus in the circulation at low levels. The CD8 cells rises transiently while CD4 cells fall but5 again recover (almost at least). The loss of these CD4 cells may result from DIRECT INFECTION of T cells in the circulation. Although antibodies lower HIV in blood, infection persists in the lymph nodes and in macrophages

2. A strong immune response Virus almost disappears from circulation Good cytotoxic T cell response Soluble antibodies appear later against both surface and internal proteins Most virus at this stage comes from recently activated (dividing) and infected CD4+ cells CD4+ cell production compensates for loss due to lysis of cells by virus production and destruction of infected cells by CTLs 2. A strong immune response

3. A latent state Latency of virus and of symptoms Virus persists in extra-vascular tissues Lymph node dendritic cells Resting CD4+ memory cells (last a very long time - a very stable population of cells) carry provirus Persistent infection with no or minor symptoms: Night sweats, generalized lymphadenopathy, diarrhea Virus persists as provirus in resting memory T cells. Reactivation of cells occurs contributing to overall viral load but this does not at this stage significantly affect CD4 cell number. Nevertheless, CD4 cells drop in number throughout infection

4. The beginning of disease Massive loss of CD4+ cells CD4+ cells are the targets of the virus Cells that proliferate to respond to the virus are killed Dendritic cells present antigen and virus to CD4 cells Epitope variation allows more and more HIV to escape from immune response just as response wanes Apoptosis of CD4+ cells HIV patients with high T4 cell counts do not develop AIDS 4. The beginning of disease

5. Advanced disease - AIDS CD8+ cells destroy more CD4+ cells CD4 cell loss means virus and infected cells no longer controlled As CD4+ cells fall below 200 per cu mm virus titer rises rapidly and remaining immune response collapses CD8+ cell number collapses Opportunistic infections Death in ~2 years without intervention 5. Advanced disease - AIDS Also neuroplogical manifestations, lymphoid neoplasms Opportunistic infects occur when CD4 cells drop below 300 cells per cu mm Mechanism of this loss is still uncertain

HIV and AIDS Good correlation between number of HIV particles measured by PCR and progression to disease

HIV and AIDS Viral load predicts survival time

progression to disease HIV and AIDS CD4 cell count is not a good predictor of progression to disease

Laboratory Diagnosis ELISA Western Blot Analysis (gp41, p24) OraQuick (rapid screening immunoassay) PCR (very sensitive and specific method)

Anti-HIV Strategies Highly Active Anti- Retroviral Therapy HAART: Two nucleoside analog RT inhibitors and 1 protease inhibitor Now also: Two nucleoside analog RT inhibitors and 1 non nucleoside

HAART has greatly slowed death rate Remember! Education led to leveling off of rate of increase in AIDS HAART has greatly slowed death rate The fact that fewer people are dying per year from the infection means that the number of HIV-infected people in the population is rising!!! Unless education continues to be successful and unless we can cure infected people of virus, the problem of virus spread, and will continue to be, with us