HIV Video Notes

I.

II.

Trial of T cell therapy for B-cell ALL (chemo ineffective) CTL019

a. Remove & engineer patient T cells to target all B cells (chimeric antigen receptor T cells)
b. Must add IVIG therapy afterward
c. Side effect: cytokine release syndrome (flu-like sx)
HIV & AIDS
i. Total: 78 million infections, 39 million deathes
b. Beginnings
i. 1981 Pneumocystis in homosexual men, CMV, thrush
ii. Clusters of Kaposis sarcoma or opportunistic infections
iii. Also transmitted at birth and heterosexually
c. HIV is a lentivirus
i. Isolated 1983 from LN in Paris
ii. 1984 blood test developed
iii. E microscopy revealed HIV to be lentivirus
d. Retroviruses
i. Lymphotrophic: HTLV-1,2,3,4
ii. HIV-1,2
1. Equine infectious anemia virus isolated in early 1900s
e. Structure
i. Glycoprotein w/envelope
ii. + strand, two copies
iii. Complex genome: many proteins, regulatory enzymes
f. AIDS
i. Syndrome: occurrence together of a characteristic group / pattern
ii. Stats
1. 600,000 deaths in US
2. 1.2 million infected in US, 14% unaware
3. 50,000 new infxn per year
4. 70% men, 30% women
5. 50% in young people (<25 years old)
6. Skewed to sub-Saharan Africa (24.7 million infected)
iii. Peak in 1997, treatments reduced deaths since then
g. Control
i. Triple-drug therapy has slowed pandemic in countries with money
ii. No cure (cant clear virus
iii. No vaccine (cant prevent)
iv. Latently infected hematopoietic progenitor cells persist
v. Resistance is common
vi. Drugs are expensive
vii. AIDS is becoming a third world disease
h. Out of Africa
i. Common in Kinshasa and Kigali (Zaire & Rwanda), where 90% of sex workers
were infected
ii. In 1960/70s, virus located in central Africa
iii. Serum sample from DRC adult male (1959) found HIV+ in 1998
iv. LN sample from DRC female HIV+ (1960)
v. Sequencing differed by 12%, already diversifying
i. HIV-1 diversity Four groups
i. Group M (main) 99%

j.

k.

l.

m.

n.

o.

1. 9 subtypes: A K and CRFs

a. CRFs (circulating recombinant forms), of which there are 48
types
b. Sex workers infected many times, recombination occurs,
selecting for fitness
c. Type D dies faster
d. Shedding of type C in female genital tract is higher
i. Black heterosexuals
e. Type B: 96% of white homosexuals in south Africa
f. F, H, J, K have limited transmission
ii. Group O (outlier) - <1%, limited to Cameroon, Gabon, neighbors
iii. Group N 13 cases, Cameroon
iv. Group P 2 cases, Cameroon
v. All from independent transmission event of SIV to humans
Evolution
i. HIV-1 evolves in one direction to numerous subtypes and recombinants
ii. Can reconstruct sequence of progress by looking at distribution (sequencing)
iii. More diverse in Africa
iv. Founder effect: subtype will PREDOMINATE in at-risk group / population
1. Associated with locations & modes of transmission
Origin of HIV-1
i. Chimps got SIV from old world monkeys (do not get sick)
ii. SIV isolated from chimp in 1989 (Pan troglodytes & schweinfurthii)
1. Transmitted via sexual intercourse, mom-child
iii. Types M and N came from 2 separate cross-species transmissions
1. From Pan troglodytes troglodytes
iv. Types O and P came from gorillas
1. Gorillas got it from chimps
Phylogenetics
i. Common sequence ancestors of Gag, Pol, and Env genes
1. Validates origin theories
2. Ruled out P.t. schweinfurthii
Spread of HIV-1
i. Leopoldville many migrants and traders
1. Cut hunter in 1921 >>> brothel >>> STD clinic w/non-sterile syringes
ii. Haitian doctors volunteered to be Belgian Congo doctors
1. Transmitted disease to Hatian doctors to enter western world
When did SIV infect humans?
i. 4 separate crossover events
1. M, O: first three decades of 20th century
2. N, P: more recent
ii. Why did only one cross-species infection spread?
1. European colonization of Africa
2. Large population centers, prostitution, movement of males for labor
3. Introduction of health care / colonial medicine (injections)
a. Egypt at turn of 20th century schistosomiasis treatment (re-used
syringes) spread HCV to millions
Transmission
i. Not particularly infectious (only sexual contact, IVDU, transfusions)
1. Male-male transmission more common in US
ii. Fluids

1. Plasma, semen, vaginal-cervical have highest density

a. Also CSF, ear secretion, feces, milk, saliva, sweat, tears, urine
b. Both cell free virus and infected cell transmission
iii. Probability
1. Higher with presence of genital ulcer disease
a. HSV infection upregulates receptors for HIV in genital tract
2. Higher with higher viral load (RNA copies / mL)
iv. Risk by groups
1. Male to male: 1in 10 to 1 in 1600
2. Male to female: 1 in 200 to 1 in 2000
3. Female to male: 1 in 700 to 1 in 3000
4. Transfusion: 95%
5. Needle sharing: 1 in 250
6. Accidental needle stick: 1 in 200
a. With AZT postexposure prophylaxis: 1 in 10,000
7. Mother to infant (w/o AZT): 1 in 4
8. Mother to infant (w/AZT): 1 in 10
v. HIV-infectivity reduced by:
1. Air drying
2. Heating
3. 10% bleach of 70% alcohol
4. pH extremes (<6 or >10)
vi. Co-receptors
1. CD4 and CXCR4 or CCR5
p. Primary HIV-1 infection
i. Virus-dendritic cell interaction with NO activation
1. Via DC-specific Icam-3 grabbing nonintegrin >>>
ii. Delivery to LNs where it actively replicates, as well as in other 2* lymphoid
tissue
1. Viremia w/dissemination
iii. Down-regulation of replication by immune response
iv. Viral set point reached after 6 months
q. Clinical characteristics
i. 50-90% symptomatic 5-30 days after exposure
1. Flu-like sx lasting 14 days + LAD, rash, WL, ulceration, meningitis
2. Leukopenia, thrombocytopenia, elevated AST/ALT
3. RNA peaks during this time
ii. Asymptomatic phase (long
1. Sporadic fatigue, WL, LAD, thrush, leukoplakia, shingels
2. Establishment of reservoirs
3. Continuous, low virus production & evolution
iii. Sites
1. GALT infection
a. Destruction of lymphoid cell aggregates
2. Blood
3. Lymphoid progenitors (contain latent virus)
r. Established HIV infection
i. Acute replication throughout course
ii. GALT, CNS, genital tract major reservoir of infection
iii. 10^9 virions made /destroyed each day
iv. T1/2 of HIV in plasma is 6 hours, short as 30 min

s. Variable courses
i. Typical progressors
ii. Rapid progressors
iii. Non-progressors (never get AIDS with low viral load)
iv. Elite Controllers
1. Normal CD4 and undetectable (<50 copies /mL) viral loads in the
absence of ART
2. 1 in 300 infected
3. Favorable HLA types (B57 and B27) and T cell responses to Gag
4. Persistent viremia
5. Not associated with attenuated viruses
t. Immune cell dysfunction
i. Low CD4, CD8 increases
1. IL-2 and IFNy decrease
ii. B cells have poor Ag response and produce autoantibodies
iii. APCs decrease, poor Ag presentation & Fc receptor function
iv. NK cytotoxicity decreases
u. AIDS
i. Less than 200 CD4 T cells/uL
1. thrombocytopenia
ii. Opportunistic pathogens
1. Pneumocystis, Toxoplasma, Isospora, Cyrptosporidium, microsporidia
2. Mycobacteria, Treponema
3. Candida, Cryptococcus, Histoplasma
4. CMV, HSV
iii. Immune activation: HIV replicates better in T cells
iv. Malignancies: EBV lymphoma, Kaposis sarcoma, anogenital CA
v. Neurological sx: aseptic meningitis, myelopathies, neuropathies, AIDS dementia
complex
1. Consequence of virus entering CNS, crossing BBB, infect astrocytes &
microglia
2. Cytokines render neurons ineffective
v. HIV & Cancer
i. 40% of infected
ii. Dysregulation of immune system
1. Absence of immune surveillance
2. High cytokine levels (mitogens) lead to proliferation, replication of
oncogenic viruses, and angiogenesis
w. Kaposis sarcoma
i. 20% of HIV-1 infected homosexual men, 2% of HIV-1 women
ii. Human Herpesvirus 8 is necessary for development of KS
x. HIV-1 vaccine is it possible?
i. Antibodies do not limit infection
ii. HIV-1 escapes from neutralizing antibodies
1. High mutation rate, evasion, plasticity
iii. RV144 in Thailand
iv. Broadly neutralizing antibodies
1. Identified in 20% of HIV-1 pts
2. Recognize conserved epitopes in Env glycoprotein
3. Takes a long time to make (B cell education)

III.

v. Immunophophylaxis
1. Clone gene encoding Ab, put in virus vector (adeno-associated)
2. Inoculate humanized mouse
3. Most did not make any viruses (100% protection
4. Now in phase 1 human trials
vi. Immune clearance of SIV in macaques
1. Viral antigen in CMV vector
2. Inoculate monkey
3. 50% protection
y. HIV-2
i. Isolated Guinea-Bissau, has 30-40% identity with HIV-1
1. Restricted to West Africa
ii. Less virulent & transmissible; most do not progress to AIDS
iii. Crossover event from Sooty Mangabey
1. 8 distinct lineages, each arising from separate infection
Drugs
a. AZT (Zidovudine)
i. Class / Use
1. Nucleoside analog RT-inhibitor
ii. Mechanism / target
1. Thymidine analog converted to 5 triphosphage
2. Chain termination
iii. Adverse Effects
1. Anemia and malaise
b. Raltegravir (Isentress); Merck
i. Class / Use / Mechanism
1. Integrase inhibitor
2. Metabolized by glucouronidation
ii. Adverse Effects
1. Allergic reactions
2. Liver toxicity
c. SB-728-T (zinc finger DNA-binding protein nuclease); Sangamo
i. Class / Use / Mechanism
1. CCR5 gene modifier that prevents expression in CD4 T cells
d. Maraviroc (Selzentry); Pfizer
i. Class / Use / Mechanism
1. Allosteric modulator of CCR5, prevents gp120 binding
e. Enfuvirtide (Fuzeon); Genentech
i. Class / Use / Mechanism
1. Binds gp41, preventing fusion pore structure / entry
ii. Adverse Effects
1. Hypersensitivity / allergy
2. Peripheral neuropathy, insomnia
f. Indinavir (Crixivan); Merck + Ritonavir, Nelfinavir
i. Class / Use / Mechanism
1. Protease inhibitor, prevents condensation of capsid
ii. Adverse Effects
1. GI upset
2. Malaise / fatigue
3. Kidney stones

4. HLD

HAART = highly active antiretroviral therapy

HAART regimen can consist of three or four drugs of different class. Typically, it includes 2
NRTIs along with 1 NNRTI, PI (protease inhibitor) or INSTI (Integrase strand transfer
inhibitors= integrase inhibitor).
o Prefered regimens recommended by the Department of Health and Human Services
(DHHS) include:
tenofovir/emtricitabine and raltegravir (an integrase inhibitor)
tenofovir/emtricitabine and dolutegravir (an integrase inhibitor)
abacavir/lamivudine (two NRTIs) and dolutegravir for patients who have been
tested negative for the HLA-B*5701 gene allele
tenofovir/emtricitabine, elvitegravir (an integrase inhibitor) and cobicistat
(inhibiting metabolism of the former) in patients with good kidney function (gfr
> 70)
tenofovir/emtricitabine, ritonavir, and darunavir (both latter are protease
inhibitors)
Use of these multidrug regimens has resulted in substantial reductions in progression to AIDS,
opportunistic infections, hospitalizations, and death.
The results/effectiveness of HAART are monitored through plasma HIV RNA level and CD4 cell
counts.
Goal of HAART- maximal suppression of HIV RNA.
o Suppression of plasma viremia will also prevent the selection of drug-resistant mutations
and allows for improvements in immunologic function (as measured by the CD4 cell
count).
g.