HIV Flashcards
Terminology
-HIV, AIDS, ART, Viral Load, CD4 count
HIV – human immunodeficiency virus
AIDS – acquired immune deficiency syndrome; an advanced stage of HIV disease when opportunistic infections (OI’s) occur
ART – antiretroviral therapy; a combination of at least three drugs that directly act against viral enzymes
Viral Load (VL) – the concentration (number of copies per mL plasma) of HIV RNA detectable in the bloodstream. Goal of ART is viral suppression
CD4 count – the concentration (number per microliter of blood) of circulating CD4+ T-cells - a marker of immune suppression
HIV Epidemiology
Map of HIV-1 (2017)
Untreated HIV Infection Time Course
Plasma HIV-1 RNA titers generally peak 1 week following the onset of symptoms and decline to steady-state levels by 2 months after infection.
HIV Infection Upon Treatment Time Course
A normal range for CD4 cells is about 500-1,500 cells per cubic millimeter of blood.
With treatment can achieve substantial reconstitution of CD4+ T cell counts
Figure of more people living with HIV with the introduction of ART in 1995
High Risk Groups for HIV Infection in US
First cases of HIV
- Kinshasa, Democratic Republic of Congo
- Tissue sample from male in 1959
- Lymph node biopsy from woman in 1960
- Haiti•Individuals returning from work in DRC 1969 and 1972
- United States
- Teenage boy in St. Louis 1969
Mammalian Retroviruses
It turns out that HIV is similar to many other retroviruses that infect other primates and other mammals. In particular, HIV-2 is very similar to a SIV in sooty mangabeys (SIVsmm), and HIV-1 is very similar to a SIV in chimpanzees (SIVcpzPtt = SIV chimpanzee Pan troglodytes troglodytes).
Subgroups of HIV
Shown here is a phylogenetic tree for the main human subtypes of HIV-1 along with gorilla and chimpanzee SIV genomes.
HIV-1 subtype M is the one causing the global pandemic.
Subtypes N, O, and P are rare, restricted to Africa, and arose from different parent SIV strains.
Zoonotic origins of epidemics/pandemics
When viruses jump to a new host there is the potential for severe disease, because the new host has not evolved defenses against the virus. The flip side is that the virus is usually not well-adapted to its new host, which is why we don’t usually catch animal diseases. But as these diseases illustrate, when it does happen it can cause significant illness.
HIV from chimpanzees
Ebola from fruit bats
MERS (Middle East respiratory syndrome) from camels (limited person-to-person spread, so far)
SARS from unknown source (likely bats), efficient person-to-person spread
Avian influenza from poultry (limited person-to-person spread, so far)
HIV-1 vs HIV-2
- There are actually two HIV viruses that infect humans, HIV-1 and HIV-2
- And each of those has various sub-types
- HIV-1 is what most people mean when they say HIV
- HIV-2 is less common, found mainly in West Africa
- HIV-2 is somewhat less aggressive in its clinical course, less likely to be transmitted, had a different origin
- For this class, we discuss HIV-1
HIV - Transmission
HIV - Transmission
Mode (Risk)
- Sex (0.04 – 1.4%) Mainly blood to blood contact but can also be via bodily fluids. Increased risk: anal sex>vaginal sex>oral sex
- Intravenous drug use i.e., sharing needles (0.6%). Viral load in index patient matters a lot.
- Mother-to-child (Up to 35 to 45%). Higher maternal viral load, increased risk for transmission.
- Blood transfusion (>90%)
- Needle-stick injuries (0.3%-0.6%)
HIV - Genome Type and General Structure
- HIV is an RNA virus and it is a retrovirus, meaning it makes DNA from RNA.
- Harbors two linear copies of (+) ssRNA genome.
- Reverse transcriptase converts RNA into DNA
- DNA then integrates into the host genome
- Spherical
- Cone-shaped capsid inside an outer envelope
- Capsid contains the viral genome, enzymes (reverse transcriptase, integrase, and protease), and tRNA primers
HIV Life Cycle
- 1) Binding: Free virus binds to a CD4 cell via the CD4 receptor and a co-receptor, CCR5 or CXCR4
- Binds using its viral envelope glycoprotein (gp120)
- CCR5 is used as the co-receptor in early infection. CCR5 is on cells of the monocyte lineage, including macrophages and dendritic cells.
- CXCR4 is used as the co-receptor after years of infection (after gp120 mutates). CDCR4 is on T cells. The switch from CCR5-tropic virus to CXCR4-tropic virus is associated with dropping T cell counts and progression of disease.
- 2) Fusion: Virus fuses with the cell and releases its contents into the cytoplasm
- 3) Reverse Transcription: Viral reverse transcriptase transcribes the RNA viral genome into DNA. Provides opportunity for mutation.
- (+) RNA is like mRNA = can be translated into protein
- Reverse Transcriptase turns viral RNA into cDNA, then makes a complementary DNA strand. Once you have the double stranded DNA it can be integrated into the host. The integrated DNA form of the virus is called the provirus.
- 4) Integration: The enzyme integrase puts the DNA into the host genome
- Can integrate anywhere, but a preference is for actively read areas.
- 5) Replication:
- 6) Assembly/Packaging:
- •Viral RNA and proteins made using host machinery
- New virions packaged and bud off the host cell
- Proteins are cleaved by protease, which changes immature virions to mature virions
- 7) Budding: - virus released from the cell.
Natural Immunity to HIV
Some people have a variant form of CCR5, called CCR5-delta32, that makes them resistance to HIV infection. They are relatively immune NOT absolutely immune. A 32 bp deletion in the CCR5 molecule. The deletion on just one allele leads to normal infection, but delayed progression while deletion on both alleles provides resistance to infection.
The Retrovirus Genome: 3 Main Genes
- Gag – capsid, matrix, and nucleocapsid (antigens). Core structural proteins.
- Pol – reverse transcriptase, protease, integrase. Viral enzymes.
- Env – glycoproteins (for the envelope). Envelope structural proteins.
- All retroviruses have these three genes
- HIV has additional genes, called accessory genes, that help it evade and destroy the immune system. They are important in HIV pathogenesis
HIV - Diagnostic Testing
-Current testing algorithm
Two basic methods – antibody-based or PCR-based
- PCR – measures copies of viral RNA in the blood. Called a direct test
- ELISA/Western Blot – detects antibodies to HIV. Called an indirect test.
Current Testing Algorithm
- Test for antibodies and the p24 antigen by ELISA (a combination test). This is the current screening test. If there is suspicion for acute infection, can also do a viral load (PCR) test, but even for that there is a week or so delay so if there is high suspicion then they should be tested again.
- If you are tested early in infection (only a few weeks in) you may test negative by an antibody test
- If acute HIV is suspected, viral load (PCR) test can be done
- Turns positive a few days before the p24 antigen test
- Positive in 7 to 10 days after infection
- Viral load testing is used mainly to monitor response to therapy
- Goal: undetectable viral load
Stages of HIV
- Acute HIV – occurs days to 4 weeks after transmission.
- Often, but doesn’t always occur.
- Marked by (often looks like mono):
- fever
- sore throat
- rash
- lymphadenopathy
- Coincides with a high level of virus in the bloodstream
- i.e., Very contagious but person doesn’t know they are infect yet
- Seroconversion (positive antibody test) usually occurs within 4 weeks but can take up to 6 months)
- Asymptomatic infection – lasts 8-10 years (usually)
- Viral load relatively stable – “set-point”
- CD4 count gradually declines
- Early symptomatic infection
- General symptoms – weight loss, diarrhea, neuropathy (tingling in hands and feet)
- Frequent or recurrent infections – thrush (Candida infection of mucosal membranes), shingles (VZV)
- Advanced HIV (AIDS)
- T cell drops (CD4 < 200 cells/mm3) or opportunistic infection (OI). T cell count could be slightly above 200 but if the patient also has an OI then they would still be considered to have AIDS. A normal range for CD4 cells is about 500-1,500 cells per cubic millimeter of blood.
- Symptoms include:
- wasting
- dementia
- pneumonia
- meningitis
- diarrhea
- skin rashes
T-Cell Count and Susceptibility to Disease
Factors Leading to Drug Resistance
- Virus
- High replication rate
- High mutation rate
- Latent reservoirs of HIV
- Nearly all drug resistance is due to target modification
- Patient
- Poor adherence
- Toxicity or inconvenience. New drugs are much better tolerated.
- Drug
- Inadequate potency
- Inadequate durability
- Drug-drug interactions
- Poor tolerability
Viral Reservoirs
- Viral Reservoirs are areas in the body where the body can persists
- ART can generally make the viral load undetectable
- No virus detected by PCR of the blood
- But viremia comes back if ART is stopped… so it must be coming from somewhere
- Latent virus integrated into the genome
- More likely in cells in tissues the drugs do not reach well
- E.g., brain, bone, testes, ovaries
- Resting CD4 T cells. Not very accessible to therapy b/c all of the drugs depend on stopping processes during replication
