Transcript retroviridae Enveloped RNA virus

Human Immunodeficiency
Virus
An Overview
AIDS- US
RACE/Ethnicity of AIDS Patients

Strong
correlations to IV
drug use.
AIDS by region
Transmission groups
3 principle core
groups that spread
HIV:
1. Prostitutes and the
men who use them.
2. Men (women)who
engage in anal sex.
3. Intravenous drug
abusers

Epidemiology
1. Sexual transmission - male homosexuals (60% spread from anal
intercourse)are the largest risk group in N. America and Western
Europe. In developing countries, heterosexual spread constitute the
most important means of transmission, often due to prostitution.
2. Blood/blood products - IV drug abusers represent the second largest
AIDS patient groups in the US and Europe. Often men (90%) infected
are part of this group and 10% of them are in both group 1 and 2.
3. Vertical transmission - the transmission rate from mother to the
newborn varies from around 15% in Western Europe to up to 50% in
Africa. Vertical transmission may occur transplacentally route,
perinatally during the birth process, or postnatally through breast milk.
Younger than 13 yrs old !?@

Births and ?
Teenagers!!!!!! Helloooo!

25% of newly
reported HIV
(+) cases are
reported in
this age each
year!
WHY???
Human Immunodeficiency Virus

Acquired Immunodeficiency syndrome first described in 1981

HIV-1 isolated in 1984 and described to the public in 1985

Belong to the lentivirus subfamily of the retroviridae

Enveloped RNA virus

Genome consists of 9200 nucleotide base pairs (HIV-1):

Gag, pol, env proteins for viral packaging

Other regulatory genes ie. tat, rev, vif, nef, vpr and vpu
HIV particles
•Viral Membrane surrounds a capsid
•Two RNA molecules connected to a
reverse transcriptase molecule.
•Gp120 antigen receptor binds to CD4+
cells in the immune cells.
•Remember from the movie that Gp41
“harpoons” the CD4+cells it will infect. It
comes through the gp120 envelope
protein.
•A second antigen contact must be made
with the CCR5 or CXCR4 cytokine
receptor.
Replication
1.
The first step of infection is the binding of gp120 viral antigen to the
CD4 or CXCR receptor of the cell: Helper T cells, Killer T cells,
dendritic cells, or macrophages...... Immune system cells!
2.
2. Followed by penetration (fusing of viral and cell membranes) and
uncoating of the viral capsid takes place in the cytoplasm by enzymes.
3. The RNA genome is then reverse transcribed into a DNA provirus
genome which is integrated into the cell genome in the nucleus. This
creates a latent infection period of up to a decade. Very little viral
reproduction takes place during this time.
4. This is followed by the synthesis and maturation of virus progeny.
Schematic of HIV Replication
1. Gp 120 attaches to the cell when it
connects to CD4. gp41 harpoons the
cell and allows…
2. Viral membrane and cell membrane
fuse.
3. Capsid is released into cytoplasm,
and enzymes eat away at it.
4. RNA and RT are released to make a
viral DNA molecule.
5. The DNA inserts into Host DNA as a
“provirus”. Causes a Latent
infection.
6. Up to a decade later, the provirus
will be transcribed, translated into
viral proteins, repackaged in capsid,
and released through budding.
HIV-1 Genotypes

There are 3 HIV-1 genotypes; M (Main), O (Outlayer), and N (New)

M group comprises of a large number subtypes and recombinant forms

Subtypes - (A, A2, B, C, D, F1, F2, G, H, J and K)

Recombinant forms - AE, AG, AB, DF, BC, CD

O and N group subtypes not clearly defined, especially since there are
so few N group isolates.

All genotypes are due to mutations because reverse transcriptase
makes at least one mistake every time it replicates.
What are CD4+ cells?
1. Helper T cells! What do they do?

2.
3.
Helper T cells direct the immune response to a
specific antigen.
Macrophages: eat cells that die… but these
don’t. However, if the HIV antigen presents
on surface, Killer T will eat.
Dendritic cells: Direct immune response in
lymph nodes by presenting antigens for Bcell
proliferation. Infection causes malfunction.
Viral Evasion Tactics
1. Proviral DNA inserts into cDNA and can not be detected by Tcells.
• During this latent infection, when the cell reproduces DNA, it
also reproduces vDNA=daughter cells with vDNA.
• Transcription and translation will occur sending new viruses
(huge amounts) into blood to infect new cells.
2. Large numbers of mutations due to RT being error prone is a
type of evasion. Killer T and antibodies need to constantly
catch up.
3. By infecting CD4+ cells, going to the lymph nodes is a happy
place for the virus.
HIV Pathogenesis

The profound immunosuppression seen in AIDS is due to
the depletion of T4 helper lymphocytes, which get infected
beneath the mucosal layer.

In the immediate period following exposure, HIV is present
at a high level in the blood (as detected by HIV Antigen and
HIV-RNA assays). Acute infection is about a week or so
after infection= flu like symptoms. Swelling of lymph nodes
(huge) is a sign of infection.

Most cases lead to a chronic infection. This occures about810 years post infection.
Pathology

It then settles down to a certain low level (set-point) during
the incubation period. During the incubation period, there
is a massive turnover of CD4 cells, whereby CD4 cells
killed by HIV are replaced efficiently. CD4 cell count
should be around 1200/ml at a time.

Eventually, the immune system succumbs and AIDS
develops when killed CD4 cells can no longer be replaced
(witnessed by high HIV-RNA, HIV-antigen, and low CD4
counts).

Viral loads usually are 1000-1000000/ml.
Opportunistic Tumours

The most frequent opportunistic tumour, Kaposi's sarcoma, is
observed in 20% of patients with AIDS. Within these tumors, the
Herpes virus 8 is observed.

Malignant lymphomas are also frequently seen in AIDS patients. B
cell lymphomas are about 100X more likely.

Neurological damage, possibly from direct infection from virus.
Opportunistic Infections
Protozoal
pneumocystis carinii (now thought to be a fungi),
toxoplasmosis, crytosporidosis
Fungal
candidiasis, crytococcosis
histoplasmosis, coccidiodomycosis
Bacterial
Mycobacterium avium complex, MTB
atypical mycobacterial disease
salmonella septicaemia
multiple or recurrent pyogenic bacterial infection
Viral
CMV, HSV, VZV, JCV
Clinical Features
1. Seroconversion illness - seen in 10% of individuals a few weeks
after exposure and coincides with seroconversion. Presents with an
infectious mononucleosis like illness.
2. Incubation period - this is the period when the patient is
completely asymptomatic and may vary from a few months to a
more than 10 years Latent Infection. The median incubation
period is 8-10 years.
3. AIDS-related complex or persistent generalized lymphadenopathy.
4. Full-blown AIDS.
Other diagnostic assays

It normally takes 4-6 weeks before HIV-antibody appears
following exposure.

A diagnosis of HIV infection made be made earlier by the
detection of HIV antigen, pro-DNA, and RNA.

However, there are very few circumstances when this is
justified e.g. diagnosis of HIV infection in babies born to
HIV-infected mothers.
Prognostic tests
Once a diagnosis of HIV infection had been made, it is
important to monitor the patient at regularly for signs of
disease progression and response to antiviral chemotherapy.
HIV viral load - HIV viral load in serum may be measured by assays
which detect HIV-RNA e.g. RT-PCR, NASBA, or bDNA. HIV viral load
has now been established as having good prognostic value, and in
monitoring response to antiviral chemotherapy.
HIV Antigen tests - they were widely used as prognostic assays. It was
soon apparent that detection of HIV p24 antigen was not as good as serial
CD4 counts. The use of HIV p24 antigen assays for prognosis has now
been superseded by HIV-RNA assays.
Treatment

Zidovudine (AZT) was the first anti-viral agent shown to have
beneficial effect against HIV infection. However, after prolonged
use, AZT-resistant strains rapidly appears which limits the effect of
AZT.

Combination therapy has now been shown to be effective,
especially for trials involving multiple agents including protease
inhibitors. (HAART - highly active anti-retroviral therapy)

The rationale for this approach is that by combining drugs that are
synergistic, non-cross-resistant and no overlapping toxicity, it may
be possible to reduce toxicity, improve efficacy and prevent
resistance from arising.
Anti-Retroviral Agents




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Nucleoside analogue reverse transcriptase inhibitors e.g. AZT,
ddI, lamivudine
Non-nucleoside analoque reverse transcriptase, inhibitors e.g.
Nevirapine
Protease Inhibitors e.g. Indinavir, Ritonavir
Fusion inhibitors e.g. Fuzeon (IM only)
HAART (highly active anti-retroviral therapy) regimens
normally comprise 2 nucleoside reverse transcriptase inhibitors
and a protease inhibitor. e.g. AZT, lamivudine and indinavir.
Since the use of HAART, mortality from HIV has declined
dramatically in the developed world.
Prevention





The risk of contracting HIV increases with the number of sexual partners. A
change in the lifestyle would obviously reduce the risk.
The spread of HIV through blood transfusion and blood products had virtually
been eliminated since the introduction of blood donor screening in many
countries.
AZT had been shown to be effective in preventing transmission of HIV from
the mother to the fetus. The incidence of HIV infection in the baby was
reduced by two-thirds.
The management of health care workers exposed to HIV through inoculation
accidents is controversial. Anti-viral prophylaxis had been shown to be of
some benefit but it is uncertain what is the optimal regimen.
Vaccines are being developed at present but progress is hampered by the high
variability of HIV. Since 1987, more than 30 HIV candidate vaccines have
been tested in approximately 60 Phase I/II trails, involving more than 10,000
healthy volunteers. A phase III trial involving a recombinant gp120 of HIV
subtype B was reported in Feb 2005 to be ineffective in preventing HIV
infection.