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Flashcards in HIV lecture Deck (54):
1

First case of HIV was?

1981 traced back 1959

2

Virus isolated HIV1 was in 1983, and confirmed cause
of AIDS?

1984

3

HIV2 was isolated in?

1986

4

Chimpanze is HIV? Sooty Mangabey is HIV?

HIV1 – Chimpanze
HIV2 – Sooty Mangabey

5

HIV belongs to which family?

Belongs to lentivirus subgroup of retrovirus family

6

What does the HIV virus infect?

Viruses infects white blood cells (lymphocytes and monocytes)

7

What is the entry port for HIV?

CD4 and CCR5 are the entry port

8

HIV-2 is ___% similar to HIV-1

HIV-2 is 55% similar to HIV-1

9

HIV-2 is?

* Prominent cause of AIDS in parts of West Africa and India
– Has appeared in the U.S.
* Distinct mechanisms of transmission compared to HIV-1

10

HIV attacks variety of cell types. Most critical are?

Helper T-cells and macrophages.
– Attached to CD4 surface receptor

11

What happens after HIV entry?

1) After entry, DNA copies of RNA genome produced using reverse transcriptase viral enzyme
2) DNA copy integrates and hides on host chromosome (Lysogeny)
3) In activated cells virus leaves cell genome and kills cell (Lytic cycle)
4) Releases additional viruses to infect other cells
5) Eventually immune system becomes too impaired to respond

12

HIV is spread primarily by:

Transference of cells and fluids when having sex with a person who has HIV. All unprotected sex with someone who has HIV contains some risk.
– Unprotected receptive sex is riskier (3.0%) than unprotected insertive sex (0.25%).
– Unprotected anal sex (5%) is riskier than unprotected vaginal sex (3%)

13

Transmission of HIV

1) Having multiple sex partners or the presence of other sexually transmitted diseases (STDs) can increase the risk of infection during sex. Unprotected oral sex can also be a risk for HIV transmission, but it is a much lower risk than anal or vaginal sex.
2) Sharing needles, syringes, rinse water, or other equipment used to prepare illicit drugs for injection.
3) Being born to an infected mother—HIV can be passed from mother to child during pregnancy, birth, or breast- feeding.

14

Less common modes of transmission include

1) Being “stuck” with an HIV-contaminated needle
2) Receiving blood transfusions
3) Being bitten by a person with HIV
4) Contact between broken skin, wounds, or mucous membranes
5) There is an extremely remote chance that HIV could be transmitted during “French” or deep, open-mouth kissing.

15

HIV Transmission
It is not spread by

Air or water.
Insects, including mosquitoes.
Saliva, tears, or sweat.
Casual contact like shaking hands or sharing dishes.
Closed-mouth or “social” kissing.

16

HIV Symptoms

– Appear after incubation period of 6 days- 6 weeks
– Usually consist of fever, headache, sore throat, muscle aches, enlarged lymph nodes and generalized rash
– Some develop CNS symptoms
– Range from moodiness and to seizures and paralysis
– Symptoms constitute acute retroviral syndrome (ARS) (Typically subside in 6 weeks)
– Acute illness followed by asymptomatic period
* Period may end with persistent enlargement of lymph nodes (Lymph adenopathy syndrome (LAS))
– Immunodeficiency symptoms include fever, weight loss, fatigue and diarrhea (Referred to as AIDS-related complex (ARC))

17

Destruction of immune system Helper T-cells by HIV can occur via multiple mechanisms

– Lysis following HIV replication
* Can’t account for complete devastation that results from disease
– Attack by HIV-specific cytotoxic CD8+ T lymphocytes
* Lymphocytes will attack and lyse infected cells
– Natural killer cells
* Play a role in cell destruction Lysis following HIV replication
– In nearly 100% of all cases immune system slowly loses ground to virus
– Peripheral CD4+ count steadily falls to nearly 50 cells/μl/year
* Symptoms usually appear when count falls below 200 cells/μl
* Reactivation of latent diseases occur when count falls below 50 cells/ μl.

18

Epidemiology of HIV

1) Unprotected sexual intercourse major factor in spread
* Men who have sex with men, followed by women and minorities.
* Survey indicates before arrival of AIDS 33% to 40% of MSM had more than 500 lifetime partners
* By 1984 two thirds were infected; of those one third had AIDS
2) Next most important mode of transmission is through blood and blood products
* By 1984 over 50% of hemophiliacs in U.S. were infected
* 10% - 20% of their sexual partners were HIV positive
3) Third most important mode of transmission is mother to infant
* One in 10 pregnant HIV-positive women will miscarry – Oflive-borninfants,15%-40%willdevelopAIDS
 Breast-feeding carries significant risk of mother-infant transmission

19

Epidemiology of HIV

1) Unprotected sexual intercourse major factor in spread
* Men who have sex with men, followed by women and minorities.
* Survey indicates before arrival of AIDS 33% to 40% of MSM had more than 500 lifetime partners
* By 1984 two thirds were infected; of those one third had AIDS
2) Next most important mode of transmission is through blood and blood products
* By 1984 over 50% of hemophiliacs in U.S. were infected
* 10% - 20% of their sexual partners were HIV positive
3) Third most important mode of transmission is mother to infant
* One in 10 pregnant HIV-positive women will miscarry
* Of live-born infants, 15% - 40% will develop AIDS
* Breast-feeding carries significant risk of mother-infant transmission

20

Persons at increased risk for HIV

1) Injected drug users who have shared needles
2) Persons who received blood transfusions or pooled blood products between 1978 and 1985
3) Sexually promiscuous men and women (prostitutes, drug abusers, and homosexual/bisexual men)
4) People w/history of hepatitis B, syphilis, gonorrhea, or other sexually transmitted diseases that may be markers for unprotected sexual intercourse w/mult. partners
5)

21

Persons at increased risk for HIV

1) Injected drug users who have shared needles
2) Persons who received blood transfusions or pooled blood products between 1978 and 1985
3) Sexually promiscuous men and women (prostitutes, drug abusers, and homosexual/bisexual men)
4) People w/history of hepatitis B, syphilis, gonorrhea, or other sexually transmitted diseases that may be markers for unprotected sexual intercourse w/mult. partners
5) People who have had blood or sexual exposure to any of the people listed

22

HIV prevention and treatment

– No approved vaccine and most people infected are unaware
– Virus on surfaces can be inactivated with commercially available disinfectants and heat at 56°C for more that 30 minutes
* Viruses in dried blood or pus may be more difficult to inactivate
– Knowledge of transmission greatest tool for control
– Use of condoms not 100% effective but have been shown to decrease transmission
– Avoidance of practices that favor HIV transmission

23

HIV Treatment

Treatment directed at “cocktails” of drugs
– Combination of reverse transcriptase inhibitors and protease inhibitors
* HAART = highly active antiretroviral therapy
– Reverse transcriptase inhibitors fall into two categories
1) Nucleoside reverse transcriptase inhibitors: Zidovudine (AZT), stavudine (D4T) and lamivudine (3TC)
2) Non-nucleoside reverse transcriptase inhibitors: Nevirapine, efavirenz and delavirdine

24

Protease inhibitors

* 6 in use
 Act late in HIV replication to prevent packaging of viral proteins

25

Protease inhibitors

* 6 in use
* Act late in HIV replication to prevent packaging of viral proteins

26

HAART

* Does not cure AIDS
* Viremia becomes undetectable in approximately 50% of cases
– Will reappear in absence of treatment
– Many strains fail to respond to HAART due to resistance

27

HIV vaccine prospects

– Currently no approved vaccines
– In theory vaccine could be used in two ways:
1) Prevention vaccine: Immunize uninfected individuals against disease
2) Therapeutic vaccine: Boost immunity of those already infected
– Successful vaccine must
1) Produce both mucosal and blood stream immunity
2) Get around HIV variability and stimulate cellular and humoral immunity

28

HIV vaccine prospects: Attenuated agent must not

1) Be capable of turning into disease-causing strain
2) Be oncogenic
3) Stimulate an autoimmune response
4) Must not cause production of “enhancing” antibodies that could aid in the passage of HIV into the body’s cells
– Finally, vaccine should induce neutralizing antibodies against free virions and prevent direct spread of HIV from cell to cell
– Vaccine trial in humans has been undertaken for at least 10 experimental vaccines

29

Kaposi’s Sarcoma

Unusual tumor arising from blood or lymphatic vessels in multiple locations
– Common in men of Mediterranean and Eastern European descent
* Not as a sign of immunodeficiency
– Tumor began to appear in young men with HIV
* 2000 times higher than period before HIV
* So common among AIDS patients became AIDS-defining condition

30

Kaposi’s Sarcoma

Unusual tumor arising from blood or lymphatic vessels in multiple locations
– Common in men of Mediterranean and Eastern European descent
* Not as a sign of immunodeficiency
– Tumor began to appear in young men with HIV
* 2000 times higher than period before HIV
* So common among AIDS patients became AIDS-defining condition
– Human herpesvirus-8 (HHV-8) detected in sarcomas
– Virus infects endothelial cells that line blood and lymphatic vessels
– Persists mostly in latent form
– Presence of virus associate with 2 dramatic changes that result in tumor formation
– Cells assume spindle shape and proliferate
– Extensive formation of new blood vessels occurs

31

B-Lymphocytic Tumors of the Brain

–B-cell lymphomas 60 to 100 times more common in AIDS patients compared to general public
– Intense, sustained replication of lymphoid cells is constant feature of HIV
– Lymph node enlargement reflects proliferation of lymphoid cells in response to high level unregulated cytokine release
– Replication of T cells occurs to replace those destroyed by HIV
– Epstein-Barr virus plays roll in B-cell lymphomas associated with AIDS
– Lymphomas rarely occur in brain except with AIDS patients

32

Cervical and Anal Carcinoma

– Cancer of uterine cervix in women and of anus in women and homosexual men strongly associated with human papillomavirus (HPV) types 16 and 18
– HPV transmitted during sexual activity
* Virus infects cervical and anal epithelium
* Appears to cause increased replication of cells via blocking of cellular gene responsible for controlling cell growth
* HPV replication increases with decline of host immunity

33

Pneumocystosis Symptoms

– Typically begins slowly with gradually increasing shortness of breath and rapid breathing
– Fever is usually slight or absent
– 50% of patients have non- productive cough
– Skin and mucous membranes becomes dusky due to poor oxygenation of blood – This can be fatal

34

Pneumocystosis
1) Causative agent
2) Pathogenesis

1) Causative agent
– Pneumocystis carinii
– Tiny fungus belonging to phylum Ascomycota
– Formerly considered a protozoan
– Differs from many fungi in cell wall components
* Consequently resistant to many fungal medications
2) Pathogenesis
– Spores of organism are inhaled into lung
* Attach to alveolar walls
– Alveoli fill with fluid, mononuclear cells and organisms
– Alveolar walls become thickened and scarred
* Interferes with free passage of oxygen

35

Pneumocystosis prevention and Treatment

– Disease used to occur in four-fifths of AIDS patients
* Was leading cause of death
* Disease largely preventable with regular doses of trimethoprim-sulfamethoxazole (TxS)
* Among the best medication for treating disease along with oxygen support
* Reduced mortality rate from nearly 100% to 30%
– After treatment patient must receive preventive medication indefinitely
* Or until achieve sustained rise in CD4+ T-cell above 200 cells/μl

36

Toxoplasmosis Causative agent

Causative agent:
– Toxoplasma gondii
– Banana-shaped protozoan
– Worldwide distribution
– Infects most warm-blooded animals
* Including household pets and domestic farm animals
– Definitive host is cat or other feline
* Organism reproduces in cat intestinal lining
* Offspring shed in feces
– Cyst form of organism can remain viable for months or years

37

Toxoplasmosis Symptoms

– Immunologically normal
* Acquired from eating raw or undercooked meat or exposure to cat feces
* Most infections asymptomatic
* Those with symptoms usually display symptoms like those of mononucleosis
– Sore throat, fever, enlarged lymph nodes and spleen
– Symptoms subside over weeks or months and do not require treatment
– Rarely life-threatening illness develops due to heart or CNS involvement

38

Toxoplasmosis Symptoms in unborn children

– Unborn children
* Disease of unborn results from almost half of maternal infections that occur during pregnancy
* Fetal disease during first trimester least common but most severe
* Often results in miscarriage
* Babies born live may have severe birth defects
* Later may develop seizures or manifest mental retardation
– 2/3 cases occur in last trimester
– Effects are usually less severe
* Retinitis can be big problem
* Less common are seizures and mental retardation

39

Toxoplasmosis Symptoms in Immunodeficient patients

1) Commonly life threatening
2) Brain involvement in form of encephalitis in more than 50% of cases
– Manifested by
 Confusion
 Weakness
 Impaired coordination
 Seizures
 Stiff neck
 Paralysis
 Coma

40

Cytomegalovirus Disease causative agents

– Cytomegalovirus (CMV)
– Enveloped, double-stranded DNA virus
* Looks like other herpes viruses
– Cells infected by the virus are two or more times the size of uninfected cells
– Envelope is acquired as virion buds through Golgi apparatus membrane
– CMV can lyse infected cell and produce active infection or can become latent and later reactivated

41

Cytomegalovirus Disease Symptoms

– Follow pattern similar to toxoplasmosis
– Acute infections in immunocompetent patients usually asymptomatic
* Adolescents and young adults may develop illness resembling mononucleosis
– Severe damage can occur to fetus if mother develops illness during pregnancy
* Congenital cytomegalic inclusion disease
– Characterized by jaundice, large liver, anemia, eye inflammation and birth defects

42

Cytomegalovirus Disease Symptoms

– Blindness most feared complication of illness in immunodeficient individuals
– Other symptoms include
* Fever
* Loss of appetite
* Painful joints and muscles
* Rapid, difficult breathing
* Ulcerations of the gastrointestinal tract with bleeding
* Lethargy and paralysis
* Dementia
* Coma and death

43

Cytomegalovirus Disease Prevention and Treatment

– No approved vaccine
– Use of condoms shown to reduce risk of sexual transmission
– Immunocompromised should avoid day care centers and should wash hands if exposed to saliva, urine and feces
– Ganciclovir decreases incidence of retinitis by 50% in HIV patients
– Ganciclovir implants delay progression to blindness
– Combination drug therapy with ganciclovir and foscarnet reduce severity of CMV disease
* Both medications have serious side effects
– Ganciclovir- bone marrow suppression
– Foscarnet- kidney impairment

44

Mycobacterial Diseases Causative agent

– Mycobacterium avium complex (MAC) caused by
M. avium and M. intracellulare
– Growth rate is almost as slow as M. tuberculosis
– Easily distinguished using biochemical testing and nucleic acid probes

45

Mycobacterial Diseases Symptoms

– Immunologically normal individuals are generally asymptomatic
* Elderly particularly those with underlying lung disease may develop chronic productive cough and lesions on the lung
* Children sometimes develop enlarged lymph nodes on the neck
* Easily treated with surgery to remove
* Immunocompromised have slowly progressing symptoms ranging from chronic productive cough to fever, sweats, weight loss, abdominal pain and diarrhea

46

Mycobacterial Diseases Pathogenesis

– Organisms enter body via inhalation or through gastrointestinal tract
– Phagocytized by macrophages
* Resist destruction by inhibiting acid production in phagosome
– Bloodstream carries organism to other sites in the body
– Intact cellular immunity clears organism
* Disease is localized
– Immunocompromised have widespread disease
– Little or no inflammation is produced
– Clinical effect is slow decline in patient health
* Does not produce quick lethal effect

47

Mycobacterial Diseases Epidemiology

– Widespread in natural surroundings
* Found in water, food, soil and dust
– In U.S. prevalent in Southeast, parts of Pacific Coast
and North Central region
– Some strains are important pathogens in chickens and pigs
– Most common bacterial cause of generalized infection in AIDS patients
– Most infections from environmental sources
* Person-to-person spread uncommon

48

Mycobacterial Diseases Prevention and Treatment

– No effective measures to prevent disease
– Clarithromycin is recommended for HIV patients with low CD4+ cell counts
* If bacteriemia develops patients given combination therapy
– Clarithromycin and ethambutol

49

Mechanisms of Action of Antiviral Drugs
Available antiviral drugs effective specific type of virus
– None eliminate latent virus
Targets include

Targets include
– Viral uncoating
– Nucleoside analogs
– Non-nucleoside polymerase inhibitors
– Non-nucleoside reverse transcriptase inhibitors
– Protease inhibitors
– Neuraminidase inhibitors

50

Viral uncoating

– Drugs include amantadine and rimantadine
– Similar in chemical structure and mechanism of action
* Mode of action is blocking uncoating of influenza virus after it enters cell
– Prevents severity and duration of disease
* Resistance develops frequently and may limit effectiveness of drug

51

Non-nucleoside polymerase inhibitor

– Inhibit activation of viral polymerases by binding to site other than nucleotide binding site
* Example = foscarnet and acyclovir
– Used to treat CMV and HSV

52

Non-nucleoside reverse transcriptase inhibitor

Inhibits activity of reverse transcriptase by binding to site other than nucleotide binding site
* Example = nevirapine, delavirdine, efavirenz
– Used in combination to treat HIV

53

Protease inhibitor

Inhibit HIV encoded enzyme protease
* Enzyme essential for production of viral particles
* Examples = indinavir and ritonavir
– Used in treatment of HIV

54

Neuraminidase inhibitor

Inhibit neuraminidase enzyme of influenza
– Enzyme essential for release of virus
– Examples = zanamivir and oseltamivir
– Zanamivir administered via inhalation
– Oseltamivir administered orally