Heme: 3:00-4:00
Scribe: Sunita Jagani
Tuesday , October 27, 2000
Proof: Sheena Harper
Dr. Bell
HIV
Page 1 of 5
He mumbled throughout the lecture and the audio was difficult to hear. I typed whatever I could make out.
I. Introduction [S1]: Most of you know about this. Until 1983, it wasn’t really in the news. Management of the patients
has progressed.
II. AIDS History [S2-3]
a. AIDS is Acquired Immune Deficiency Syndrome.
b. First case, Sentinel case was reported in June 1981.
c. Throughout 1981, additional cases reported in large US cities.
d. In 1982, association with high risk groups recognized (4 H’s):
i. Homosexual men, Heroin users, Hemophiliacs, Hatians.
ii. Don’t really know why Hatians are included. Maybe because of similar risk factors as Africans.
e. It became clear that this was an infectious process transmissible through blood and sexual contact.
f. In 1983, Human immunodeficiency virus was identified (HIV-1); the virus that causes AIDS.
g. In 1985, Blood test developed which could detect HIV prior to the development of AIDS.
III. AIDS [S4-5]
a. AIDS is the disease caused by the retrovirus Human Immunodeficiency Virus (HIV) characterized by a profound
immunosuppression leading to opportunistic infection, secondary neoplasms, and neurologic manifestations.
b. There are about 900,000 + cases in the US. It’s a national problem and worldwide problem.
c. It is the second leading cause of death among men between ages 25 – 44
d. It is a global problem:
i. 60 million worldwide with 20 million deaths
ii. 42 million living with HIV/AIDS; 70% in Africa, 15% in Asia
IV. Epidemiology [S6-8]
a. Five groups of adults in US at risk of developing AIDS.
b. Homosexual or bisexual men
i. Account for over 50% of the population
ii. Category in decline because of understanding the transmission of this disease
c. Intravenous drug abusers
i. Account for about 25%
d. Hemophiliacs
i. Particularly those who received large amounts of factor prior to 1985 before blood testing
ii. Account for less than ~0.5%
e. Recipients of blood and blood components who are not hemophiliacs
i. Accounts for about ~1%. It does include organs from infected donors. Transmission through transplants
can happen.
f. Heterosexual contacts of other high risk groups
i. Accounts for about ~10 % chiefly through contact with IV drug abusers
1. Women who are involved with men who are IV drug abusers
2. 33% of new cases
3. Heterosexual transition is on the rise
g. 6% without recognized risk factors
h. 2% of AIDS cases occur among children under the age of 13
i. Transmission different in this age group
i. 90% due to transmission of virus from mother to child
ii. 10% related to transfusion; Hemophiliacs or others receiving blood products prior to 1985
V. Transmission [S9]
a. From risk groups:
i. It can be transmitted through sexual contact
ii. Transmitted through Parenteral inoculation-injected directly into the bloodstream or transfusion
iii. Transmission from infected mothers to newborns
VI. Sexual Transmission [S10-12]
a. Sexual transmission is the most important mechanism for transmission.
b. Worldwide accounts for 75% of cases.
c. Virus carried in semen, within lymphocytes and free and also with new evidence of direct attachment to sperm
d. Direct sexual transmission by direct inoculation into the blood vessels
i. Abrasions in rectal or oral mucosa
1. Historically transferred by homosexual men
ii. Taken up by dendritic cells or CD4+ cells within the mucosa that can be infected with the virus.
Heme: 3:00-4:00
Scribe: Sunita Jagani
Tuesday , October 27, 2000
Proof: Sheena Harper
Dr. Bell
HIV
Page 2 of 5
e. Heterosexual transmission increasingly common- usually transmitted from male to female. Usually female sex
partners of male IV drug users in the US
f. Sexual transmission is the dominant mode of HIV infection in Asia and Africa
g. Female to male transmission is more common in these areas
i. Increased Concurrent sexually transmitted disease for a number reasons.
ii. Male to female STD, you have increased inflammatory cells that within the semen can carry the virus. With
STD’s there is also an increased risk of a mucosal breakage, so ulceration, where you have direct
exposure to the fluids to the blood supply.
h. Sexual transmission enhanced by coexisting sexually transmitted disease
i. Ulceration in cases of syphilis and herpes.
ii. Increased numbers of infected inflammatory cells in semen
VII. Parenteral Transmission [S13]
a. Three major groups
i. IV drug abusers through needle sharing.
ii. Hemophiliacs
1. Direct transmission
2. There was high risk before screening. There was a pool of donors that the factor was obtained from.
There was multiple exposures of a single dosage of the factor.
3. Recombinant factor now commonly used
iii. Recipients of blood transfusion
1. Screening of blood since 1985
a. Direct testing of each unit of blood donated
2. Screening of donors based on history
3. Voluntary donor pool
a. Important for blood safety because people can self-excluded because of high-risk behaviors.
There is no pressure to give.
i. Worse thing that can happen, someone gets hurt in a church group, and they feel
morally obligated to give blood, which can be bad if they don’t want to due to high-risk
behaviors. There is a check box that will say do not donate.
ii. A voluntary donor pool is important because even though we do test all the blood, the
tests aren’t perfect.
4. Risk now less than 1 per 2 million units of blood of having a infected unit
a. Because of current protocol
VIII. Mother to Infant Transmission [S14]
a. Mother to infant transmission by :
i. In utero by transplacental spread
ii. Can occur during delivery through infected birth canal
iii. After birth by ingestion of breast milk
iv. Rate for perinatal transmission ~25% prior to retroviral therapy, now very low levels of transmission. If we
know that mother is infected, the rate is low.
b. SQ- What’s the risk of getting HIV infection from plasma donation? A: Risk should be minimal since the virus is
carried in the cells, and there are no cells in plasma. We lose the voluntary component with plasma donation
because people are paid for plasma donation.
IX. Etiology [S15]
a. HIV is caused by human retrovirus
b. Two related forms:HIV-1 and HIV-2
i. HIV-1 most common in US, Europe, Central Africa. HIV-2 most common in West Africa and India
c. Blood tests are available for both forms and blood collected for transfusion is routinely screened for both
viruses.
X. Structure of HIV [S16-18]
a. HIV is a spherical with cone-shaped core surrounded by a lipid envelope derived from the host cell membrane
b. The Core is composed of
i. p24, the major capsid protein, important in testing because p24 is the most readily detected viral protein
and is widely targeted for testing for infection
ii. Nucleocapsid protein p7/p9
iii. Two copies of genomic RNA
iv. Three viral enzymes: protease, reverse transcriptase, and integrase
c. Matrix protein, p17, surrounds the core
d. Envelope:
Heme: 3:00-4:00
Scribe: Sunita Jagani
Tuesday , October 27, 2000
Proof: Sheena Harper
Dr. Bell
HIV
Page 3 of 5
i. Host lipid bilayer
ii. Studded with glycoproteins gp120 and gp41. These two are actually in association. Gp 41 is a
transmembrane protein that anchors gp120.
1. Critical for infection
e. [S18] Cartoon showing the structure. The core with p24 capsid protein, genome within the core, and the
envelope with gp120 anchored by gp41 through the nuclear envelope.
XI. HIV Genome[S19-20]
a. Fairly simple Schematic of the genome.
b. Considerable variability in certain parts of the genome
i. Particularly Envelope glycoproteins
ii. Causes problems because limits humoral immunity and hard to development of vaccine
XII. Pathogenesis [S21]
a. Two major targets
i. Immune system
ii. Central nervous system
b. The mechanism of infection is similar in both.
c. The infection causes immunosupression due to infection and loss of CD4+ T-cells and impairment of function of
helper T cells.
d. The infection enters the body and infects T cells, dendritic cells, and macrophages
e. It spreads to in lymphoid tissues where it may remain latent
f. And when its proliferative, there is development of AIDS associated with active viral replication and spread
XIII. Figure [S22]
a. This is cartoon showing that. Lymphocytes infected with HIV, spreads to the lymph nodes, where they remain
latent, until those cells are stimulated, in which case the cells proliferate and the virus proliferates, leading to the
destruction of the cells which leads to the spread to other areas .
XIV.
Life Cycle of HIV [S23]
a. CD4 is a high affinity receptor for HIV.
b. HIV virus has selective tropism for CD4+ which includes: T-cells, macrophages, and dendritic cells. T cells and
antigen presenting cells.
c. Gp120 on the surface envelope must also bind a co-receptor for the virus to enter the cell. Two well defined coreceptors: (CCR5,CXCR4)
XV. Infection of CD4+ Cells [S24]
a. Squence of infection:
i. Binding of gp120 to CD4 causing a conformational change in gp120 allowing binding of co-receptor
ii. Binding of the co-receptor causes conformation change in gp41, which leads to insertion of fusion peptide
at the terminus of the gp 41 into target cell membrane
iii. And then the Virus core is transferred into the cytoplasm of the cell
XVI.
Infection of CD4+ Cells [S25]
a. Virus with gp120 exposed on the surface, binds to CD4 which results in change, allows binding to gp120 to the
cofactor.
b. When that occurs, Gp41 introduces its terminus through the cell membrane and nuclear material goes into the
cell.
c. Individuals with defective copies of the coreceptor, if homozygous, are resistant to infection . Very uncommon;
less than 1%.
XVII. Infection of CD4+ Cells [S26-27]
a. Within any infection there are M tropic strain which uses CCR5 as coreceptor which are expressed on
monocytes and T-cells
i. Can infect both monocytes and T cells (CCR5 expressed); so infect langerhans . dendritic
b. The T tropic strain uses CXCR4 as coreceptor, only expressed on T-cells
i. Can only infect T-cells
c. Beginning of the infection the majority of the virus M tropic form to infect almost all cell types are the susceptible.
As the infection progresses, there is evolution of the virus to T tropic strain, so the T tropic strain predominates
later in infections. This is probably important for transmission becase the M tropic form has more targets to get
through the mucosal cells. You pick up an intact mucosa because of the antigen presenting cells.
d. Within cell, viral RNA undergoes reverse transcription to produce cDNA
e. cDNA integrates into host genome
f. May be latent or may be transcribed to produce infective viral particles by budding or packaging off the surface of
the cell.
g. If you extreme proliferation, then you have Extreme viral budding, and this leads to cell death or lysis
Heme: 3:00-4:00
Scribe: Sunita Jagani
Tuesday , October 27, 2000
Proof: Sheena Harper
Dr. Bell
HIV
Page 4 of 5
XVIII. Life Cycle of HIV [S28]
a. Binding, transmission of the genome, integration into the host genome where it can remain latent until the cells
is stimulated by some infection. An antigen activates some T cell, and the virus proliferates because it has been
activated.
XIX.
T-Cell Immunodeficiency [S29]
a. Productive infection and viral replication is the major mechanism by which HIV causes lysis of CD4+ T-cells.
Virus begins to replicate, causes budding, which causes lyses.
b. Activated, 100 billion viral particles produced per day leading to lysis of 1-2 billion T-cells per day, which at first
is not noticeable because there is a lot of T-cells and lymphoid tissue. Eventually it will be too much.
c. Massive loss that cannot be compensated
XX. T-Cell Immunodeficiency [S30]
XXI.
Lysis of the cells. There are other mechanisms as well. HIV can cause destruction of lymphocytes.
XXII. Natural History of Infection [S31-33]
a. Acute infection
i. High levels of virus production with widespread seeding of lymphoid tissues
ii. Antiviral immune response
iii. Patients are experience nonspecific symptoms including sore throat, fever, myalgias, weight loss (flulike)
b. Chronic phase:
i. Latent with low level replication in the lymphoid tissues
ii. This may last several years
iii. Assymptomatic or develop generalized lymphadenompathy
c. Progression to AIDS
i. Fever, fatigue, weight loss, diarrhea initially, and then serious opportunistic infections
XXIII. Figure [S34]
a. These graphs show the progression of the infections.
b. You can see CD4 lymphocyte count and titer, drops with initial infection, stabilizes because the viral immune
response, then t-cell count drops - thyermia occurs, patients experiences an opportunistic infection when the
white count drops below a certain point.
c. You can see the viral particles in the plasma, as the immune response to the virus occurs, antibodies, anti-p24,
cytotoxic lymphocytes specific for the peptide, then there’s a drop in the viral particles in the early late phase,
then eventually we get proliferation and an increase viral titer.
XXIV. Clinical Features of AIDS [S35]
a. Initially, patients have fever, weight loss, diarrhea, generalized lymphadenopathy
b. Opportunistic infections result in the majority of deaths
c. AIDS defining infections:
i. Pneumocystis –pulmonary infection, more common 1st infection seen, 20 percent of patients have it before
highly reactive anti-viral therapy was developed.
ii. candidiasis, cryptococcosis, coccidioidomycosis, histoplasmosis, mycobacteriosis, nocardiosis, CMV,
Herpes, Varicella-zoster
XXV. Candidiasis [S36]
a. Most common fungal infection with AIDS
b. Common presentation is oral cavity (thrush) and esophagus
c. Oral Candidiasis a sign of immunologic decomposition
XXVI. Neoplasms Associate with AIDS [S37]
a. Kaposi sarcoma- we talked about in the vascular lymphomas
b. Non-Hodgkin B cell lymphoma
c. Cervical cancer in women
d. Anal cancer in men
e. 25-40% of patients will develop a malignancy
f. Something in common. All are associated with Oncogenic DNA viruses:
i. episi -scaroma is specifically associated with HHV-8
ii. Some narcotic t-cell lymphomas associated with EBV-epistein barr virus
iii. HPV-cervical cancer in woman, anal cancer in men
XXVII. CNS Involvement [S38]
a. 90% with neurologic involvement at autopsy
b. 50% with clinical neurologic dysfunction
i. Peripheral neuropathies or progressive dementia
XXVIII. Treatment [S39]
a. Antiretroviral therapy:
Heme: 3:00-4:00
Scribe: Sunita Jagani
Tuesday , October 27, 2000
Proof: Sheena Harper
Dr. Bell
HIV
Page 5 of 5
i. It improves CD4 T-cell counts, reduces opportunistic infection, and maintains latent phase.
ii. Active infection if treatment is stopped. The treatment has been extremely successful.
iii. Life expectancy is 24+ years following therapy with initiation of therapy as opposed to 4 years when Dr. Bell
was in medical school.
iv. AIDS is more chronic disease process.
v. Much better prognosis than before.
vi. Treatment of AIDS of patient is from beginning to death $680,000 with optimal therapy. Can be more
expensive if you develop severe infections.
b. There is currently no vaccine: None available
i. Viral polymorphism limiting vaccine development.
XXIX. End [29:22]