Designer antibodies that bind to both CD3 receptors on T-cells and HIV proteins on infected cells have shown promise in laboratory experiments as a potential approach to eliminating HIV reservoirs and achieving a cure. These bispecific antibodies act to bridge infected cells and T-cells, activating latent virus and marking the infected cells for destruction. While early studies in mice were problematic, more recent studies using improved antibody designs have activated and lysed latent HIV-infected human cells in test tubes without significant safety issues. However, successfully translating this approach to safe and effective human trials faces challenges including fully understanding and targeting all HIV reservoir sites and gaining acceptance within HIV/AIDS communities.

1. Designer Antibodies and HIV:
A Step Towards a Cure
Angel Pichardo, Beau Smith, Halle Burns, Jake Harris

2. Intro
● CART has dramatically reduced the number of AIDS-related deaths and has
increased the life expectancy of those infected with HIV.
● A variety of approaches have been attempted to fully eradicate the virus but the
persistence of HIV reservoirs has always allowed for viral RNA levels to rebound.
● One approach, involves shocking CD4 cells into activating the latent HIV virus
and using another drug to destroy the activated viruses. Has only been performed
in test tubes.
● This novel approach involves in the use of bispecific antibodies that bind to CD3
receptors and HIV proteins.
● “Stuffs prey into lion’s mouth”

3. The Structures
CD3 Receptor
● Involved in cytotoxic
T-cell activation
● Part of T-cell
Receptor (TCR)
found on all T-cells
https://en.wikipedia.org/wiki/CD3_(immunology)

4. The Structures
HIV-1 Env Proteins
● gp120
● gp41
● Displayed on surface
of CD4+ cells when
infected
https://commons.wikimedia.org/wiki/File:HI-Virion-en.png

5. The Structures
Antibodies (Sung et al.)
● 2-Fab regions
● anti-CD3 antigen-binding
site
- Derived from hXR32
(humanized anti-CD3ε
mAb)
● anti-HIV antigen-binding
site
- A32 binds to gp120
- 7B2 bind to gp41
Figure 1 from Sung et al. (2015)

6. The Structures
Antibodies (Pegu et al.)
● 2-Fab regions
● Anti-CD3 antigen-binding site
- Single chain variable fragment
(scFv) on light chain
● anti-HIV antigen-binding site
- VRC07 protein
- Targets gp120
- Highly active mutation
(G54W)
- Binds to HIV-1-Env proteins
Figure 1a from Pegu et al. (2015)

7. Mechanism: Dual Affinity Re-targeting
CD3: Plays several roles in the elimination of latent CD4+ cells:
A. Induces proliferation of CD4 cells via CD3 binding
B. Helps bridge CD4 and CD8 cells via CD3 binding
C. Provides necessary stimulation for ANY CD8 lysis of CD4 cell
gp41 and gp120:
A. Help bridge CD4 and CD8 cells via binding of gp41 or gp120 of infected cells
When both occur simultaneously, the product is greater than the sum of the parts:
A. More latent CD4s are activated and healthy CD4s are recruited as effectors

8. Prospects
❖ 1999 Study: Not so great
➢ Over activation
■ Inflammatory reaction, Kidney failure and other organ damage, Seizures
➢ Serious complications
❖ New Study: Promising, but no human trials
➢ DART
➢ New antibodies are bispecific vs. antibodies with two arms
➢ Caution against possibility of over activation of T cells

9. Issues With The New Studies
❖ Mouse trials
➢ One of the studies was conducted in Mice
■ Xenogenic Mouse Antigens → Chronic Hyperstimulation
■ Engrafted Human T Cells Compared To Those Educated Completely In Humans → Antigen
Specificity
■ HIV-1 interactions with different cell types
● Variability in engraftment and levels of human and murine cells
❖ Target Cells
➢ Potential Facilitation of Synapse Between Infected and Uninfected CD4 TCells

10. Access
❖ Cost of treatment
❖ Justice
➢ Geography
➢ Status
❖ Human Trials

11. Ethics
❖ Human Trials
➢ When is it safe
➢ What is the sample population
➢ Who would volunteer
❖ AIDS is no longer a death sentence
➢ Treatment
❖ Prevention or Cure
➢ PrEP
➢ Resources

12. Complications and Barriers
❖ What cells make up the HIV reservoir
➢ Unknow aspect → Are all reservoirs depleted?
❖ HIV/AIDS Community
➢ Skepticism
➢ Fear
➢ Misunderstanding

13. Works Cited
Cohen, Jon. "Designer Antibodies May Rid Body of AIDS Virus." Science Magazine. American Association For
The Advancement of Science, 20 Oct. 2015. Web.
Sung, J. et al. Dual-Affinity Re-Targeting proteins direct T cell–mediated cytolysis of latently HIV-infected cells.
J Clin Invest. 2015;125(11):4077–4090. doi:10.1172/JCI82314.
Pegu, A. et al. Activation and lysis of human CD4 cells latently infected with HIV-1. Nat. Commun. 6:8447 doi:
10.1038/ncomms9447 (2015).
"PRE-EXPOSURE PROPHYLAXIS (PrEP)." AIDS.gov. U.S. Department of Health and Human Services, n.d. Web. 29 Apr. 2016.