Immunodeficiencies HIV/AIDS

Immunodeficiencies Due to impaired function of one or more components of the immune or inflammatory responses. Due to impaired function of one or more components of the immune or inflammatory responses. Problem may be with: Problem may be with: –B cells – T cells – phagocytes –or complement

Immunodeficiencies may be: Congenital (primary) Caused by a genetic abnormality Acquired (secondary) – more common Normal physiologic changes – aging Severe malnutrition or selective deficiency Caused by another illness: Diabetes Cancer Viral infection

Main cause is disruption of lymphocyte function Stem cell defect : Prevent normal lymphocyte development and total failure of immune system Lymphoid organ dysfunction: prevents maturation of B or T cells or final maturation of B cells = lack of specific class of immunoglobulins

Hallmark: Tendency to develop unusual or recurrent, severe infections. Deficiencies in T cells suggested by recurrent infections with viruses, fungi and yeast. Deficiencies in B cells suggested by recurrent infections with certain bacteria or viruses affected by humoral immunity

Routine treatment No live vaccines No live vaccines Be aware breaks in skin for routine blood tests can cause septicemia Be aware breaks in skin for routine blood tests can cause septicemia At risk for Graft-versus-Host disease At risk for Graft-versus-Host disease

Acquired Immunodeficiencies Nutritional deficiencies Iatrogenic (caused by physician, hospital, etc) drugs immunosuppressive therapy chemotherapy and radiation Trauma – esp. burns Stress

HIV/AIDS Human immunodeficiency virus Human immunodeficiency virus Acquired immunodeficiency syndrome Acquired immunodeficiency syndrome Two forms : HIV1 and HIV-2 Two forms : HIV1 and HIV-2 High mortality rate High mortality rate Asymptomatic carriers Asymptomatic carriers Logarithmic increase in number of patients Logarithmic increase in number of patients Medical community cannot control spread Medical community cannot control spread

Transmission Sexual transmission Sexual transmission Contaminated needles – sharing Contaminated needles – sharing Blood products Blood products Transplacental or nursing Transplacental or nursing

History Probably arose in central Africa before 1931 Probably arose in central Africa before 1931 Believed to be a monkey virus mutated to affect humans Believed to be a monkey virus mutated to affect humans Found Ab’s against HIV in serum samples taken in 1960’s Found Ab’s against HIV in serum samples taken in 1960’s First cases reported 1980’s in male homosexuals First cases reported 1980’s in male homosexuals

In 1995, the number 1 cause of death for ages 25 – 44 in U.S. In 1995, the number 1 cause of death for ages 25 – 44 in U.S. Heterosexual transmission is increasing in the U.S. and is the most common route of transmission outside of the U.S. Heterosexual transmission is increasing in the U.S. and is the most common route of transmission outside of the U.S. Greater than 50% of cases are women Greater than 50% of cases are women

In 2008, CDC adjusted its estimate of new HIV infections because of new technology developed by the agency. Before this time, CDC estimated there were roughly 40,000 new HIV infections each year in the United States. In 2008, CDC adjusted its estimate of new HIV infections because of new technology developed by the agency. Before this time, CDC estimated there were roughly 40,000 new HIV infections each year in the United States.

High Risk Individuals Homosexual/bisexual men Homosexual/bisexual men I.V. drug abusers I.V. drug abusers Recipients of blood products Recipients of blood products Female partners of bisexual men/ I.V. drug abusers Female partners of bisexual men/ I.V. drug abusers Children of infected mothers Children of infected mothers

Today, more people than ever before are living with HIV/AIDS. CDC estimates that about 1.1 million persons in the United States are living with HIV or AIDS. An estimated 21% of these persons do not know that they are infected: not knowing puts them and others at risk. Today, more people than ever before are living with HIV/AIDS. CDC estimates that about 1.1 million persons in the United States are living with HIV or AIDS. An estimated 21% of these persons do not know that they are infected: not knowing puts them and others at risk.

Health care workers are at risk Health care workers are at risk –Nurses –Clinical lab techs Most HIV + workers infected off duty Most HIV + workers infected off duty TAKE PRECAUTIONS !!! TAKE PRECAUTIONS !!!

HIV is a fragile virus. It cannot live for very long outside the body. As a result, the virus is not transmitted through day-to-day activities such as shaking hands, hugging, or a casual kiss. You cannot become infected from a toilet seat, drinking fountain, doorknob, dishes, drinking glasses, food, or pets. You also cannot get HIV from mosquitoes. HIV is a fragile virus. It cannot live for very long outside the body. As a result, the virus is not transmitted through day-to-day activities such as shaking hands, hugging, or a casual kiss. You cannot become infected from a toilet seat, drinking fountain, doorknob, dishes, drinking glasses, food, or pets. You also cannot get HIV from mosquitoes.

HIV is primarily found in the blood, semen, or vaginal fluid of an infected person. HIV is transmitted in 3 main ways: HIV is primarily found in the blood, semen, or vaginal fluid of an infected person. HIV is transmitted in 3 main ways: –Having sex (anal, vaginal, or oral) with someone infected with HIV –Sharing needles and syringes with someone infected with HIV –Being exposed (fetus or infant) to HIV before or during birth or through breastfeeding

Pathogenesis Retrovirus – RNA plus reverse transcriptase, integrase and protease Retrovirus – RNA plus reverse transcriptase, integrase and protease Attachment: Binds to CD4 receptors (T H ) and chemokine receptors gp 120 or gp 41 Attachment: Binds to CD4 receptors (T H ) and chemokine receptors gp 120 or gp 41 Internalization – RNA enters the cell Internalization – RNA enters the cell Reverse transcriptase converts RNA → DNA Reverse transcriptase converts RNA → DNA Integrase inserts viral DNA into Host DNA Integrase inserts viral DNA into Host DNA

Viral DNA is transcribed into mRNA Viral DNA is transcribed into mRNA mRNA is translated into protein – polyprotein mRNA is translated into protein – polyprotein Cleavage of polyprotein into usable proteins Cleavage of polyprotein into usable proteins Viruses are assembled Viruses are assembled Host cell is killed as viruses are released Host cell is killed as viruses are released BUT helper T cells are replaced and viruses are killed, but CD4 cells decrease over time. BUT helper T cells are replaced and viruses are killed, but CD4 cells decrease over time.

Helper T cells Coordinate the response of both B and T cells Coordinate the response of both B and T cells Patients susceptible to infections and malignancies Patients susceptible to infections and malignancies Normally /mm 3 Normally /mm 3 Category1: > 500 cells/ μL Category1: > 500 cells/ μL Category 2: cells/ μL Category 2: cells/ μL Category 3: < 200 cells/ μL (AIDS) Category 3: < 200 cells/ μL (AIDS)

Clinical Manifestations Category A: no symptoms or persistent generalized lymphadenopathy or symptoms of primary HIV infection Category A: no symptoms or persistent generalized lymphadenopathy or symptoms of primary HIV infection Category B: symptoms of immune deficiency not serious enough to be called AIDS Category B: symptoms of immune deficiency not serious enough to be called AIDS Category C: person has AIDS defining illness (chart 15-2) Category C: person has AIDS defining illness (chart 15-2)

Clinical manifestations Infection - serologically negative Infection - serologically negative In seven days followed by acute phase in % of people lasts a few days - 2 weeks resembles influenza or mononucleosis sore throat, muscle aches, fever, swollen glands, rash, headache or meningitis In seven days followed by acute phase in % of people lasts a few days - 2 weeks resembles influenza or mononucleosis sore throat, muscle aches, fever, swollen glands, rash, headache or meningitis

Seroconversion occurs 3 – 17 weeks after infection – HIV proteins can be detected in the blood Seropositive patients have anti-HIV Ab’s circulating Following infection through blood products, in general see anti-HIV Ab’s in 4-7 weeks Following infection through sexual exposure, it may take 6-14 months for detection of anti- HIV Ab’s (one case - years)

Window period = time between infection, Ab detection: An infected person can infect others within 2 weeks of initial HIV exposure, at a time well before anti-HIV Ab’s can be detected. Average time from initial infection to AIDS is about 10 years, though this rate of development is lengthening with new treatments available.

Chronic phase – can last for years Chronic phase – can last for years –Asymptomatic –Viral load decreases –Chronic lymphadenopathy –orofacial herpes zoster, oral candidiasis –B cells make antibodies, but are ineffective –Gradual drop in T4 cells – no symptoms until below 200/mm 3

Crisis phase – ARC – AIDS-related complex Crisis phase – ARC – AIDS-related complex –CD4 count < 200 cells/ μL –Long lasting fever < 3 months –Malaise –Diarrhea –Weight loss and wasting syndrome – Multiple opportunistic infections –Persistent viral or fungal infections of the skin –Without therapy death in 2-3 years

AIDS Related Diseases AIDS: To be positive for AIDS requires positive lab test and clinical symptoms - Unusual infections or neoplasms AIDS: To be positive for AIDS requires positive lab test and clinical symptoms - Unusual infections or neoplasms Kaposi’s sarcoma Kaposi’s sarcoma Non-Hodgkins lymphoma Non-Hodgkins lymphoma Wasting syndrome Wasting syndrome AIDS dementia complex AIDS dementia complex

AIDS Related Diseases Fungal: Fungal: –Candidiasis –Cryptococcus Viral: Viral: –Herpes simplex –Herpes zoster –Cytomegalovirus

Opportunistic infections Pneumocystis carinii pneumonia Toxoplasmosis gondii Mycobacterium avium intracellulare Mycobacterium tuberculosis

Treatment Expensive: $1,200 -1,500 / month if healthy Expensive: $1,200 -1,500 / month if healthy Cocktail of 3 different meds Cocktail of 3 different meds

Treatment Restore immune function Restore immune function –Hasn’t been easy or successful: Bone marrow transplant, immunomodulators, transfusions Bone marrow transplant, immunomodulators, transfusions Prevent viral replication Prevent viral replication –Reverse transcriptase inhibitors (AZT) –Protease inhibitors –Integrase inhibitiors –Maturation inhibitors –Fusion inhibitors - newest

Difficulties with Vaccines HIV is antigenically variable HIV is antigenically variable Antibodies are not protective Antibodies are not protective Can be transmitted by cell to cell contact Can be transmitted by cell to cell contact Animal models are protected species (primates) Animal models are protected species (primates) HIV virus exclusively infects and causes disease in humans HIV virus exclusively infects and causes disease in humans

Other problems Viral DNA incorporated into host cell DNA Viral DNA incorporated into host cell DNA Virus mutates as the virus replicates Virus mutates as the virus replicates