(10/2) Chiampas Lecture: Introduction to the Human Immunodeficiency Virus (HIV) and (AIDS) HIV Etiology: A single-stranded RNA virus of the Lentivirinae subfamily

- HIV-1: More common in the US and Worldwide. Subgroups: M, N, O, P [Most Virulent!] - HIV-2: More common in western Africa. Subgroups: A, B, C, D, E, F, G [Not the Most Virulent!] ;) - Purpose: Attack the human body’s immune system, specifically CD4+, which lyse upon HIV replication - CD4+ T Cell Count: Uninfected individuals generally have 500-1500 cells/mm^3 and a 40-70% CD4/Total T

o >500 cells: Normal count, low risk of infection o 200-500: May be at a higher risk of opportunistic infection (OI) o <200: AIDS Dx. Patient will be at high risk of OIs. o OTHER FACTORS:

§ Meds: Chemotherapy, IFN therapy, Transplant meds, Steroids § Diseases: Hep B and C, Splenectomy, Coinfection with HTLV § Acute Infections: Stress, common cold, bacterial illness/infections

- Acquired Immunodeficiency Syndrome (AIDS) Dx: Once diagnosed, it is in their MR forever o CD4 T Cell Count < 200cells/mm^3, generally <14% of total T cell count o Diagnosing of one of the AIDS-defining conditions (A huge list of OI and nonsense)

§ Ex: Bacterial infections Multiple or Recurrent, Histoplasmosis, Mycobacterium avium complex - HIV-1 RNA- the surrogate marker for the Viral load. This is the most important marker

o Refers to the number of HIV copies replicating in 1ml of blood. The viral load is undetectable if the concentration of HIV-RNA is less than the lower limit of detection per the labs assay

o What’s it mean? – well the goal of treatment is to keep it as low as possible, and the lower the viral load the less likely an individual is to transmit it.

HIV Epidemiology: - Risk Factors: Unprotected Sex (especially being a receiver of intense anal sex), IV drug use, mother-child, needle

o Bodily Fluids: Blood, Semen, Vaginal, Breast Milk - Preventing Transmission: One of the most effective and reasonable à Treatment as a prevention method

o Safe Sex (Condoms reduce risk by 80%, and you could abstain if you don’t like living on the edge) o Get Circumcised ASAP, Don’t breastfeed o New Stuff: Pre/Post-Exposure Prophylaxis (PEP/PrEP)

- Lifetime Risk = Cumulative probability of HIV diagnosis from birth (Live in the US? 1 in 99 chance) Wow… o Men are 4x more likely than women, Black women 19x White women, Homesexual Male 79x Hetero

Immunology and Pathophysiology of HIV - On the HIV Virion are viral proteins, which serve as the antigens. We can test for these antigens and the

antibodies to them to diagnose HIV infection - Detection: Due to the actions of cellular immunity, we can detect HIV in our body fluids! YAY

o HIV Ag are detected earlier than Ab. The prototype Ag is p24 antigen, present on the capsid shell § 4th generation tests include the p24 antigen test combined with a 3rd generation test, and reduce

the window of detection to 10-14 days o Viral DNA is used to detect the presence of HIV

§ 5th generation tests are able to distinguish between the genetic variants of HIV - Testing and Dx: Testing for HIV has become a 2 step process – Screening and Confirmation

o Specimen: FDA approved tests exist for: Whole blood, Plasma/Serum, Oral Fluid § PrEP: Whole blood or plasma/serum samples are recommended.

o Screening: Test should be highly sensitive. If the HIV is present, test is active. With a positive result, we will test again because it is possible to get false positives. If negative, no confirmatory test is needed.

o Confirmation: Performed if at least one of the screening tests is reactive. § High specificity, if reactive à HIV is present

- HIV-1 Lifecycle o Binding: The gp120 subunit of HIV has high affinity for the CD4+ T Cell, CCR5, and CXCR4 Receptor. o Fusion: Binding induces a conformational change in the chemokine receptor, fusing the HIV Virion

particles with the T Cell membrane, permitting entry of the virion components. o Reverse Transcription: The Reverse Transcriptase (RT) enzyme that come along the ride converts the

HIV RNA into HIV DNA so that HIV DNA can enter the CD4 Nucleus o Integration: HIV Enzyme Integrase inserts the HIV DNA into the CD4 host genome o Transcript/Translate: Using host machinery, HIV makes copies of HIV proteins

o Assembly: HIV Enzyme protease cleaves the long protein chains into smaller active proteins o Budding: New HIV virus exits the CD4 T Cell, and there is CD4 T Cell Lysis L

- Pathophysiology o Clinical Stage 1: Primary/Acute Infection Period: Large amount of virus,

significant decline in CD4+, many exhibit the worst “flu-like” symptoms o Clinical Stage 2/3: Clinical Latency/Chronic Infection Period: HIV

reproduces slowly, pt may be asymptomatic. Without treatment this period lasts on average 10 years.

o Clinical Stage 3/4: AIDS: As CD4<200, without treatment the average survival time is 3 years

- Complications: Complications generally arise only in cases of untreated or poorly-controlled HIV/AIDS o Encephalopathy, Cytomegalocirus Retinitis, Pneumocystic Jiroveci Penumonia, Cervical Cancer

HIV Treatment: In 1993, combo therapies emerged, and we showed that we can prevent death by AIDs (specifically) - START and TEMPRANO trials had showed that ART therapy (anti-retroviral) should be initiated ASAP

o “Higher CD4 count at ART initiation predicts long-term likelihood of CD4 count normalization” - Early Therapy

o Benefits: Reduction in deaths, reduction in non-AIDS conditions (HD, Liver Disease, Kidney Disease), reduction in risk of HIV transmission, preservation of immunologic function

o Challenges/Concerns: Impact of AE on QoL, impact of non-adherence, cost - ART (Antiretroviral Therapy): A combination therapy with Antiretroviral (ARV) meds

o Also known as a HIV Cocktail, HIV Regimen, HAART, cART

o Combines at least 3 active ARVs from 2 different classes. Each ARV class interferes with HIV replication at a different stage of the HIV lifecycle.

o Prior to treatment: a resistance genotype must be drawn to assess for mutations

o Typical Cocktail: 2 NRTIs with a ‘3rd agent’, NEED AT LEAST 3 Active ARVs from 2 different classes.

- Goals of Therapy: Want undetectable viral load, usually can be achieved in 12-24 weeks. Want to increase CD4 count by 50-150 cells/mm^3 per year. Prevent HIV Transmission

- Adherence: Factors affecting adherence: Food requirements, dosing frequency, pill burden, AE, and access o Suboptimal adherence: Decreased virologic control, substantial increase in morbidity/mortality, and

increased risk of drug resistance. o Missing a dose provides the HIV virus a chance to make copies of itself with resistance mutations