HIV
INTRODUCTION TO HUMAN IMMUNODEFICIENCY VIRUS (HIV)
Source: CDC
Course: Evolution of Infectious Diseases, Fall 2025
Instructor: Dr. Timothy Driscoll (LSB 4204)
THE RISE OF ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS)
Late 1980: Outbreak of fungal pneumonia among homosexual men in the US.
This condition is very rare outside of immunocompromised patients.
July 1981: An extremely rare and aggressive form of cancer, Kaposi's Sarcoma, is noted in 41 homosexual men in the US.
The case fatality rate of untreated AIDS is 100%.
January 1983: Identification of a previously unknown virus from the lymph node of a pre-AIDS patient; tested positive for reverse transcriptase (RT).
The virus is named human immunodeficiency virus (HIV) following recognition by Charles Dauguet at the Pasteur Institute on February 3, 1983.
KOCH'S POSTULATES
Four criteria to determine the causative relationship between a pathogen and a disease:
The agent must be present in all individuals with the disease, but absent in healthy individuals.
The agent must be isolated from a diseased individual and grown in pure culture.
The cultured agent should cause disease when introduced into a healthy patient.
The agent must be re-isolated from the inoculated, diseased patient and identified as the same as the original agent.
Not all pathogens can be cultured (e.g., viruses, Coxiella, Rickettsia).
Some pathogens (e.g., COVID-19) do not cause disease in all individuals or require cofactors.
Some pathogens (e.g., HIV) cannot be isolated from infected individuals.
Example: Koch’s postulates were successfully used to establish that anthrax is caused by a bacterium.
DOES HIV CAUSE AIDS?
Applying Koch’s Postulates to establish causality remains a standard method in infectious disease research.
VERY EARLY EVIDENCE THAT HIV CAUSES AIDS
Early symptoms of HIV infection are flu-like and resolve within weeks.
AIDS takes years, sometimes decades, to manifest, creating a gap in establishing direct links between HIV and AIDS.
Symptoms of AIDS are inconsistent across patients, raising questions such as, "If you die with the virus, did you die from the virus?".
DEFINITIVE EVIDENCE THAT HIV CAUSES AIDS
Evidence from the National Institutes of Health (NIH)
Date: November 29, 2000
Author: National Institute of Allergy and Infectious Diseases (NIAID)
Evidence Structure
Epidemiological Association
Virtually all AIDS patients (99.93%) are HIV-seropositive.
HIV has been isolated in nearly all AIDS patients and almost all HIV-seropositive individuals at various disease stages.
Isolation
Use of PCR and other molecular techniques to document the presence of HIV genes in virtually all patients with AIDS, including early-stage patients.
Example: Transmission of HIV from a Florida dentist to six patients was documented by genetic analyses.
The dentist and four of the patients developed AIDS.
Transmission Pathogenesis
Case of eleven children infected with HIV as neonates from a single donor; eight of these children developed AIDS within 10 years.
The remaining three showed a progressive decline in cellular immunity.
Temporal and Geographic Linkage
AIDS and HIV infection are invariably linked in time and geography.
In every area where AIDS has developed, evidence of HIV infection has preceded the clinical manifestation of AIDS by several years.
Predictive Factor
Only HIV infection predicts the development of AIDS; individuals of all demographics who develop AIDS share HIV as a common factor.
HIV-seropositive individuals are 1,100 times more likely to develop AIDS-associated illnesses compared to those who are HIV-seronegative.
AIDS-Defining Illnesses
Nearly exclusive occurrence of AIDS-defining illnesses in HIV-infected individuals.
FURTHER EVIDENCE OF HIV AS CAUSE OF AIDS
Increased Prevalence of Rare Diseases
Examples include:
Pneumocystis carinii pneumonia: 107 cases pre-AIDS; 166,368 reported by 1999.
Kaposi's Sarcoma: 0.2-0.6 cases per million pre-AIDS; 46,684 cases by 1999.
Mycobacterium avium complex: 32 cases pre-AIDS; 41,873 by 1999.
Studies in Twins
In twins where one is HIV-positive and the other is not, only the infected twin develops AIDS, demonstrating the direct causal relationship.
Evidence of Repeated HIV Presence in Transfusion-acquired AIDS Cases
Transfusion-acquired AIDS cases show the presence of HIV in both the donor and recipient.
ARRIVAL OF HIV IN THE USA
Earliest verified case of HIV infection recorded in blood sample from 1959 from a man in Kinshasa, Congo.
Phylogenetic analysis traces the spread of HIV from Africa to Haiti and then to the United States.
Phylogenetic trees allow for understanding the evolution of HIV through mutation and depict relationships among various lineages.
HIV evolves rapidly, prompting studies into the reasons for this rapid evolution.
HUMAN IMMUNODEFICIENCY VIRUS (HIV)
HIV is classified as a retrovirus, meaning its genetic information flows from RNA -> cDNA -> mRNA -> protein.
Other RNA viruses directly use their genome as mRNA without producing cDNA.
Family of HIV: Retroviridae; Genus: Lentivirus.
Features:
Single-stranded, positive-sense RNA genome; includes two genome copies per virion.
Ability to integrate its genome into the host cell's genome, complicating treatment options.
Positive-sense RNA allows direct use as mRNA, raising the question of why it doesn't do so.
THE HIV GENOME
Comprises three primary polycistronic genes: gag, env, and pol which translate into 10 functional proteins:
Gag: Contains 4 capsid proteins.
Env: Contains 2 envelope glycoproteins.
Pol: Engages in replication processes and consists of proteins necessary for HIV function.
Unlike most viruses, HIV predominantly relies on the host's enzymes for replication, complicating treatment.
HIV LIFE CYCLE
Binding & Fusion
HIV envelop proteins (gp120) bind to CD4 molecules and chemokine co-receptors on host cells.
HIV has a particular tropism, favoring certain host cell types.
HIV and host cell membranes fuse, inserting the viral core into the host cytoplasm.
The viral core's uncoating allows reverse transcription of RNA to cDNA.
Proviral DNA is imported into the host nucleus.
Integration
Viral integrase nicked the host DNA permitting insertion of the HIV genome into the host chromosome.
Continuous repair and integration of viral DNA occurs through host repair enzymes.
Replication & Release
The host transcription machinery transcribes integrated DNA into RNA.
Translated polyproteins and new viral genomes form.
New (immature) HIV particles buds from the host cell.
After release, proteases cleave polyproteins into functional units, forming infectious viruses.
TREATMENT OF HIV
Entry inhibitors: Block HIV from binding to host cells.
Examples: Maraviroc, Fostemsavir.
Fusion inhibitors: Prevent membrane fusion of HIV and host cell.
Example: Enfuvirtide.
NRTIs: Nucleoside reverse transcriptase inhibitors inhibit viral RT activity preventing RNA to DNA conversion.
Example: AZT.
NNRTIs: Non-nucleoside reverse transcriptase inhibitors target RT to block conversion process.
INSTIs: Integrase strand transfer inhibitors hinder integration of viral cDNA into the host genome.
Examples: Dolutegravir, Raltegravir.
Capsid inhibitors: Disrupt the capsid preventing proper assembly.
PIs: Protease inhibitors block maturation of the virus.
Examples: Darunavir, Ritonavir.
Antiviral therapy (ART) utilizes combinations of various drug classes for efficacy.
DISTINCTION BETWEEN HIV AND AIDS
AIDS represents the terminal stage of HIV infection.
ART can effectively halt the progression from HIV to AIDS.
HIV medications may reduce viral loads to undetectable levels, but no cure exists.
Phases of HIV:
Incubation phase (2-4 weeks): Asymptomatic.
Acute phase (28 days): Flu-like symptoms with seroconversion.
Chronic phase (up to 20 years): No symptoms.
AIDS phase: Immune collapse allowing opportunistic infections.
SIGNIFICANCE OF HIV/AIDS
AIDS is considered one of the most severe infectious diseases impacting humanity.
Estimated 42 million individuals affected globally (as of 2004), with nearly a 100% case fatality rate.
In 2002, 5 million new HIV infections, predominantly in sub-Saharan Africa.
As of 2023, HIV/AIDS research funding from NIH is $3.2 billion, contrasting with $8.1 billion for cancer research.
HIV MUTATION MECHANISM
Reverse transcription of viral RNA into cDNA is characterized by a high error rate due to lack of proofreading by viral proteins.
Host DNA-dependent RNA polymerase (Pol II) transcribes new viral genomes but has lower efficiency compared to dedicated DNA polymerases.
HIV MUTATION RATE
HIV exhibits the highest mutation rate known to science, accumulating mutations at 22-52 substitutions per genome annually.
Rate of substitutions: substitutions/site/year.
In hypervariable regions of the env gene: rates increase to 26-70 per genome annually.
TYPES OF HIV
HIV-1 vs. HIV-2
Infectivity:
HIV-1: High
HIV-2: Low
Virulence:
HIV-1: High
HIV-2: Low
Heterosexual Spread:
HIV-1: Higher
HIV-2: Lower
Vertical Transmission:
HIV-1: 20-25%
HIV-2: <5%
Genetic Diversity:
HIV-1: High
HIV-2: Lower
Prevalence:
HIV-1: Global
HIV-2: Primarily in West Africa
Origin:
HIV-1: Common chimpanzee
HIV-2: Sooty mangabey
Time to AIDS:
HIV-1: ~10 years
HIV-2: >20 years
DIFFERENT HISTORIES OF HIV-1 AND HIV-2
HIV-1 and HIV-2 are closely related to different primate SIVs, indicating distinct entry points into humans.
Emergence events of HIV in humans likely occurred multiple times.
Founder effects impact the spread of the virus and its establishment in human communities.
Sampling bias affects our understanding of the HIV-1 subtype structure, influenced by collection efforts in specific geographic areas
HIV-1 group M is responsible for the majority of global infections and was predominant since its emergence around Kinshasa, Congo.